N-adamantlmethyl derivatives and intermediates as pharmaceutical compositions and processes for their preparation

ABSTRACT

The invention provides compounds of general formula (I) in which m, A, R 1  and Ar have the meanings defined in the specification; a process for, and intermediates used in, their preparation; pharmaceutical compositions containing them; a process for preparing the pharmaceutical compositions; and their use in therapy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is the national phase application under 35 U.S.C. § 371of PCT International Application No. PCT/SE02/02057, filed Nov. 12,2002, which claims priority to Swedish Application Serial No. 0103836-3,filed Nov. 16, 2001.

The present invention relates to adamantane derivatives, processes fortheir preparation, pharmaceutical compositions containing them, aprocess for preparing the pharmaceutical compositions, and their use intherapy.

The P2X₇ receptor (previously known as P2Z receptor), which is aligand-gated ion channel, is present on a variety of cell types, largelythose known to be involved in the inflammatory/immune process,specifically, macrophages, mast cells and lymphocytes (T and B).Activation of the P2X₇ receptor by extracellular nucleotides, inparticular adenosine triphosphate, leads to the release ofinterleukin-1β (IL-1β) and giant cell formation (macrophages/microglialcells), degranulation (mast cells) and proliferation (T cells),apoptosis and L-selectin shedding (lymphocytes). P2X₇ receptors are alsolocated on antigen-presenting cells (APC), keratinocytes, salivaryacinar cells (parotid cells), hepatocytes and mesangial cells.

It would be desirable to make compounds effective as P2X₇ receptorantagonists for use in the treatment of inflammatory, immune orcardiovascular diseases, in the aetiologies of which the P2X₇ receptormay play a role.

In accordance with the present invention, there is therefore provided acompound of formula

wherein m represents 1, 2 or 3, preferably 1 or 2;

-   each R¹ independently represents a hydrogen or halogen (e.g.    fluorine, chlorine, bromine or iodine) atom, preferably a hydrogen    atom;-   A represents C(O)NH or, preferably, NHC(O);-   Ar represents a group

-   one of R² and R³ represents halogen, nitro, amino, hydroxyl, or a    group selected from (i) C₁–C₆ alkyl optionally substituted by at    least one halogen atom, (ii) C₃–C₈ cycloalkyl, (iii) C₁–C₆ alkoxy    optionally substituted by at least one halogen atom, and (iv) C₃–C₈    cycloalkyloxy, and the other of R² and R³ represents a hydrogen or    halogen atom;-   R⁴ represents a group

-   X represents an oxygen or sulphur atom or a group >N—R⁸;-   n is 0 or 1;-   R⁵ represents a C₁–C₅ alkyl group which may be optionally    substituted by at least one substituent selected from hydroxyl,    halogen and C₁–C₆ alkoxy;-   R⁶ and R⁷ each independently represent a hydrogen atom, C₁–C₆ alkyl    (optionally substituted by at least one substituent selected from    hydroxyl, halogen, C₁–C₆ alkoxy, and (di)-C₁–C₄ alkylamino (itself    optionally substituted by at least one hydroxyl group)), or C₃–C₈    cycloalkyl (optionally substituted by at least one substituent    selected from hydroxyl, halogen and C₁–C₆ alkoxy); and-   R⁸ represents a hydrogen atom or a C₁–C₅ alkyl group which may be    optionally substituted by at least one substituent selected from    hydroxyl, halogen and C₁–C₆ alkoxy;-   with the provisos that:    -   (a) when n is 0, then A is NHC(O), and    -   (b) when n is 1, X represents oxygen and A is C(O)NH, then R⁶        and R⁷ do not both simultaneously represent a hydrogen atom or        do not both simultaneously represent an unsubstituted C₁–C₆        alkyl, or when one of R⁶ and R⁷ represents a hydrogen atom, then        the other of R⁶ and R⁷ does not represent an unsubstituted C₁–C₆        alkyl; and    -   (c) when n is 1, X is oxygen, sulphur or >NH and A is NHC(O),        then R⁶and R⁷ do not both simultaneously represent a hydrogen        atom or do not both simultaneously represent an unsubstituted        C₁–C₆ alkyl, or when one of R⁶ and R⁷ represents a hydrogen        atom, then the other of R⁶ and R⁷ does not represent an        unsubstituted C₁–C₆ alkyl or —CH₂CH₂OH;        or a pharmaceutically acceptable salt or solvate thereof.

In one embodiment of the invention, there is provided a compound offormula

wherein m represents 1, 2 or 3, preferably, 1 or 2;

-   each R¹ independently represents a hydrogen or halogen (e.g.    fluorine, chlorine, bromine or iodine) atom, preferably a hydrogen    atom;-   A represents C(O)NH or, preferably, NHC(O);-   Ar represents a group

-   one of R² and R³ represents halogen, nitro, amino, hydroxyl, or a    group selected from (i) C₁–C₆ alkyl optionally substituted by at    least one halogen atom, (ii) C₃–C₈ cycloalkyl, (iii) C₁–C₆ alkoxy    optionally substituted by at least one halogen atom, and (iv) C₃–C₈    cycloalkyloxy, and the other of R² and R³ represents a hydrogen or    halogen atom;-   R⁴ represents a group

-   X represents an oxygen or sulphur atom or a group >N—R⁸;-   n is 0 or 1;-   R⁵ represents a C₁–C₅ alkyl group which may be optionally    substituted by at least one substituent selected from hydroxyl,    halogen and C₁–C₆ alkoxy; and-   R⁶, R⁷ and R⁸ each independently represent a hydrogen atom or a    C₁–C₅ allyl group which may be optionally substituted by at least    one substituent selected from hydroxyl, halogen and C₁–C₆ alkoxy;-   with the provisos that:    -   (d) when n is 0, then A is NHC(O), and    -   (e) when n is 1, X represents oxygen and A is C(O)NH, then R⁶        and R⁷ do not both simultaneously represent a hydrogen atom or        do not both simultaneously represent an unsubstituted C₁–C₅        alkyl, or when one of R⁶ and R⁷ represents a hydrogen atom, then        the other of R⁶ and R⁷ does not represent an unsubstituted C₁–C₅        alkyl, and    -   (f) when n is 1, X is oxygen, sulphur or >NH and A is NHC(O),        then R⁶ and R⁷ do not both simultaneously represent a hydrogen        atom or do not both simultaneously represent an unsubstituted        C₁–C₅ alkyl, or when one of R⁶ and R⁷ represents a hydrogen        atom, then the other of R⁶ and R⁷ does not represent an        unsubstituted C¹–C₅ alkyl or —CH₂CH₂OH;        or a pharmaceutically acceptable salt or solvate thereof.

In the context of the present specification, unless otherwise indicated,an alkyl substituent or alkyl moiety in a substituent group may belinear or branched. Examples of alkyl groups/moieties containing up to 6carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl, n-hexyl and combinations of any two ormore thereof. The alkyl groups in a di-C₁–C₄ alkylamino substituentgroup may be the same or different. Further, it should be appreciatedthat in the definition of R⁵, if the at least one optional substituentis a hydroxyl or alkoxy group, it will not be attached to a carbon atomadjacent either to —X— or to —NR⁶R⁷. Similarly, in the definitions ofR⁶, R⁷ and R⁸, a hydroxyl or alkoxy moiety should not be attached to acarbon atom which is adjacent to a nitrogen atom.

In an embodiment of the invention, Ar represents a group of formula (II)or (III).

In another embodiment of the invention, Ar represents a group of formula(II).

One of R² and R³ represents a halogen (e.g. fluorine, chlorine, bromineor iodine), nitro, amino (—NH₂), hydroxyl, or a group selected from (i)C₁–C₆ alkyl, preferably C₁–C₄ alkyl, optionally substituted by at leastone (e.g. one, two, three or four) halogen atom(s) as defined above,(ii) C₃–C₈ cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl), (iii) C₁–C₆ alkoxy, preferably C₁–C₄ alkoxy, optionallysubstituted by at least one (e.g. one, two, three or four) halogenatom(s) as defined above, and (iv) C₃–C₈ cycloalkyloxy (e.g.cyclopropyloxy, cyclobutyloxy, cyclopentyloxy or cyclohexyloxy), and theother of R² and R³ represents a hydrogen or halogen atom as definedabove.

In one embodiment of the invention, one of R² and R³ represents ahalogen (such as a chlorine or bromine) atom and the other of R² and R³represents a hydrogen atom.

In an embodiment of the invention, n is 0.

R⁵ represents a C₁–C₅ (e.g. C₁–C₃) alkyl group which may be optionallysubstituted by at least one substituent (e.g. one, two, three or foursubstituents independently) selected from hydroxyl, halogen (e.g.fluorine, chlorine, bromine or iodine) and C₁–C₆, preferably C₁–C₄,alkoxy (e.g. methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexoxyand combinations of any two or more thereof).

In an embodiment of the invention, R⁵ represents —CH₂—, —(CH₂)₂—,—(CH₂)₃— or —CH₂CH(OH)CH₂—.

R⁶ and R⁷ each independently represent:

-   (i) a hydrogen atom,-   (ii) C₁–C₆, preferably C₁–C₅, alkyl optionally substituted by at    least one substituent (e.g. one, two, three or four substituents    independently) selected from hydroxyl, halogen (e.g. fluorine,    chlorine, bromine or iodine), C₁–C₆, preferably C₁–C₄, alkoxy (e.g.    methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexoxy and    combinations of any two or more thereof), and (di)-C₁–C₄, preferably    C₁–C₂, alkylamino (itself optionally substituted by at least one,    e.g. one or two, hydroxyl group(s)), or-   (iii) C₃–C₈ cycloalkyl optionally substituted by at least one    substituent (e.g. one, two, three or four substituents    independently) selected from hydroxyl, halogen (e.g., fluorine,    chlorine, bromine or iodine) and C₁–C₆, preferably C₁–C₄, alkoxy    (e.g. methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexoxy and    combinations of any two or more thereof).

In an embodiment of the invention, R⁶ and R⁷ each independentlyrepresent:

-   (i) a hydrogen atom,-   (ii) C₁–C₅ alkyl optionally substituted by at least one substituent    (e.g. one, two or three substituents independently) selected from    hydroxyl and (di)-C₁–C₄, preferably C₁–C₂, alkylamino (itself    optionally substituted by at least one, e.g. one or two, hydroxyl    group(s)), or-   (iii) C₅–C₆ cycloalkyl optionally substituted by at least one, e.g.    one or two, hydroxyl group(s).

R⁸represents a hydrogen atom or a C₁–C₅, preferably C₁–C₃, alkyl groupwhich may be optionally substituted by at least one substituent (e.g.one, two, three or four substituents independently) selected fromhydroxyl, halogen (e.g. fluorine, chlorine, bromine or iodine) andC₁–C₆, preferably C_(l)–C₄, alkoxy (e.g. methoxy, ethoxy, n-propoxy,n-butoxy, n-pentoxy, n-hexoxy and combinations of any two or morethereof).

In an embodiment of the invention, R⁸ represents a hydrogen atom or aC₁–C₃ alkyl group which may be optionally substituted by at least one,e.g. one or two, hydroxyl group(s).

In another embodiment of the invention, R⁶, R⁷ and R⁸ each independentlyrepresent a hydrogen atom or a C₁–C₅ (e.g. C₁–C₃) alkyl group which maybe optionally substituted by at least one substituent (e.g. one, two,three or four substituents independently) selected from hydroxyl,halogen (e.g. fluorine, chlorine, bromine or iodine) and C₁–C₆ alkoxy(e.g. methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexoxy andcombinations of any two or more thereof.

In a further embodiment of the invention, R⁶, R⁷ and R⁸ eachindependently represent a hydrogen atom or a C₁–C₅ (e.g. C₁–C₃) alkylgroup optionally substituted by at least one, e.g. one, two or three,hydroxyl group (s) such as —CH₃, —C₂H₅, —CH(CH₃)₂, —CH₂OH, —(CH₂)₂OH,—(CH₂)₃OH, —CH(CH₃)CH₂OH, —CH₂CH(CH₃)OH, —CH₂CH(OH)CH₃, —CH₂CH(OH)CH₂OH,—CH₂C(CH₃)₂OH, —CH(isopropyl)CH₂OH, —CH(CH₂OH)₂, or —CH₂C(CH₃)₂CH₂OH.

In an embodiment of the invention, there is provided a subset ofcompounds of formula (I), and pharmaceutically acceptable salts andsolvates thereof, in which:

-   m represents 1;-   each R¹ represents a hydrogen atom;-   A represents NHC(O);-   Ar represents a group

-   one of R² and R³ represents a halogen atom, and the other of R² and    R³ represents a hydrogen atom;-   R⁴ represents a group

-   X represents an oxygen or sulphur atom or a group >N—R⁸;-   n is 0 or 1;-   R⁵represents a C₁–C₃ alkyl group optionally substituted by at least    one hydroxyl group;-   R⁶ and R⁷ each independently represent a hydrogen atom, C₁–C₅ alkyl    (optionally substituted by one or two substituents independently    selected from hydroxyl and (di)-C₁–C₂ alkylamino (itself optionally    substituted by at least one hydroxyl group)), or C₆ cycloalkyl    (substituted by at least one hydroxyl group);-   R⁸ represents a hydrogen atom or a C₂ alkyl group substituted by at    least one hydroxyl group; and-   subject to the provisos (a), (b) and (c) mentioned above.

In another embodiment of the invention, there is provided a furthersubset of compounds of formula (I), and pharmaceutically acceptablesalts and solvates thereof in which:

-   m represents 1;-   each R¹ represents a hydrogen atom;-   A represents NHC(O);-   Ar represents a group

-   one of R² and R³ represents a halogen atom, and the other of R² and    R³ represents a hydrogen atom;-   R⁴ represents a group

-   X represents an oxygen or sulphur atom or a group >N—R⁸;-   n is 0 or 1;-   R⁵ represents a C₂–C₃ alkyl group optionally substituted by at least    one hydroxyl group;-   R⁶ and R⁷ each independently represent a hydrogen atom or a C₁–C₅    alkyl group optionally substituted by one or two hydroxyl groups;-   R⁸ represents a hydrogen atom or a C₂ alkyl group substituted by at    least one hydroxyl group; and-   subject to the provisos (d), (e) and (f) mentioned above.

Examples of compounds of the invention include:

-   N-(1-Adamantylmethyl)-5-chloro-2-{3-[(3-hydroxypropyl)-amino]propyl}isonicotinamide,-   N-(1-Adamantylmethyl)-5-chloro-2-{3-[(3-hydroxypropyl)amino]propyl}-isonicotinamide    dihydrochloride,-   N-(1-Adamantylmethyl)-2-chloro-5-{3-[(3-hydroxypropyl)amino]propyl}nicotinamide,-   N-(1-Adamantylmethyl)-2-chloro-5-(3-{[(1S)-2-hydroxy-1-methylethyl]amino}propyl)nicotinamide,-   N-(1-Adamantylmethyl)-2-chloro-5-(3-{[(1R)-2-hydroxy-1-methylethyl]amino}propyl)nicotinamide,-   N-(1-Adamantylmethyl)-2-(3-aminopropyl)-5-chloroisonicotinamide    hydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-[3-(ethylamino)propyl]isonicotinamide    hydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-({2-[(3-hydroxypropyl)amino]-ethyl}thio)isonicotinamide    hydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-(3-{[(1R)-2-hydroxy-1-methylethyl]amino}propyl)isonicotinamide,    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-(3-{[(1S)-2-hydroxy-1-methylethyl]amino}propyl)isonicotinamide,    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-{3-[(2-hydroxyethyl)amino]propyl}-isonicotinamide    hydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-{2-[(3-hydroxypropyl)amino]ethoxy}isonicotinamide,    hydrochloride-   N-(1-Adamantylmethyl)-5-chloro-2-({2-[(2-hydroxyethyl)amino]ethyl}-amino)isonicotinamide    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-[3-(isopropylamino)propyl]isonicotinamide    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-(3-{[(2S)-2-hydroxypropyl]amino}propyl)isonicotinamide,    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-(3-{[(2R)2,3-dihydroxypropyl]amino}propyl)isonicotinamide,    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-(3-{[(2S)-2,3-dihydroxypropyl]amino}propyl)isonicotinamide,    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-{3-[(4-methylcyclohexyl)amino]propyl}isonicotinamide    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-{3-[(2-hydroxy-2-methylpropyl)amino]propyl}isonicotinamide    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-(3-{[(1R)-1-(hydroxymethyl)-2-methylpropyl]amino}propyl)isonicotinamide,    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-(3-{[2-(methylamino)ethyl]amino}propyl)isonicotinamide    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-(3-{[3-(methylamino)propyl]amino}propyl)isonicotinamide    bis(trifluoroacetate),-   N-(1-Adamantylmethyl)-5-chloro-2-[3-({2-[(2-hydroxyethyl)amino]ethyl}amino)propyl]isonicotinamide    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-(3-{[2-(diethylamino)ethyl]amino}propyl)isonicotinamide    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-(3-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}propyl)isonicotinamide    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-{3-[(2-hydroxyethyl)(methyl)amino]propyl}isonicotinamide    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-{3-[(3-hydroxy-2,2-dimethylpropyl)amino]propyl}isonicotinamide    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-(3-{[(2R)-2-hydroxypropyl]amino}propyl)isonicotinamide,    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-({[3-(methylamino)propyl]amino}methyl)isonicotinamide    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-[({2-[(2-hydroxyethyl)amino]ethyl}amino)methyl]isonicotinamide    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-({[2-(methylamino)ethyl]amino}methyl)isonicotinamide    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-{3-[(2-hydroxyethyl)amino]ethyl}isonicotinamide    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-{3-[(3-hydroxypropyl)amino]ethyl}isonicotinamide    dihydrochloride,-   N-(1-Adamantylmethyl)-5-chloro-2-[3-(methylamino)propyl]isonicotinamide    hydrochloride,-   N-(1-Adamantylmethyl)-5-bromo-2-{[(2S)-2-hydroxy-3-methylamino)propyl]oxy}isonicotinamide,-   N-(1-Adamantylmethyl)-2-({3-[bis(3-hydroxypropyl)amino]propyl}amino)-3-chloroisonicotinamide    dihydrochloride,    and all pharmaceutically acceptable salts and solvates of any one    thereof.

The present invention further provides a process for the preparation ofa compound of formula (I) as defined above, or a pharmaceuticallyacceptable salt or solvate thereof, which comprises:

-   (i) when n is 0 and R⁵ represents CH₂, reacting a compound of    formula

-    wherein R¹⁰ represents —C(O)H or —CH₂L¹, L¹ represents a leaving    group (e.g. halogen, paratoluene sulphonate or methane sulphonate)    and m, R¹, R² and R³ are as defined in formula (I), or a compound of    formula

-    wherein R¹¹ represents —C(O)H or —CH₂L², L² represents a leaving    group (e.g. halogen, paratoluene sulphonate or methane sulphonate)    and m, R¹, R² and R³ are as defined in formula (I), or a compound of    formula

-    wherein R¹² represents —C(O)H or —CH₂L³, L³ represents a leaving    group (e.g. halogen, paratoluene sulphonate or methane sulphonate)    and m, R¹, R² and R³ are as defined in formula (I),-    with a compound of formula (XIII), HNR⁶R⁷, wherein R⁶ and R⁷ are as    defined in formula (I), under reductive amination conditions when    R¹⁰, R¹¹ or R¹² represents —C(O)H or in the presence of a suitable    base R¹⁰, R¹¹ or R¹² represents —CH₂L¹, —CH₂L² or —CH₂L³; or-   (ii) when n is 0, R⁵ is (CH₂)₂ and R⁶ and R⁷ are both hydrogen,    reacting a compound of formula (X) as defined in (i) above in which    R¹⁰ represents —CH₂L¹, or a compound of formula (X) as defined    in (i) above in which R¹¹ represents —CH₂L², or a compound of    formula (XI) as defined in (i) above in which R¹² represents —CH₂L³,    with an alkali metal cyanide, followed by a hydrogenation reaction;    or-   (ii) when n is 0, R⁵ is (CH₂)₂ and at least one of R⁶ and R⁷ is    other than hydrogen, reacting a compound as prepared in (ii) above    with at least one compound of formula (XIV), R¹³C(O)H, wherein R¹³    represents an optionally substituted C₁–C₆ alkyl or C₃–C₈ cycloalkyl    group as defined for R⁶ and R⁷ in formula (I), under reductive    amination conditions; or-   (iv) when n is 0 and R⁵ represents a C₃–C₅ all group optionally    substituted as defined in formula (I), reacting a compound of    formula

-    wherein R¹⁴ represents a leaving group (e.g. halogen or    trifluoromethanesulphonate) and m, R¹, R² and R³ are as defined in    formula (I), or a compound of formula

-    wherein R¹⁵ represents a leaving group. (e.g. halogen or    trifluoromethanesulphonate) and m, R¹, R² and R³ are as defined in    formula (I), or a compound of formula

-    wherein R¹⁶ represents a leaving group (e.g. halogen or    trifluoromethanesulphonate) and m, R¹, R² and R³ are as defined in    formula (I), with a compound of formula

-    wherein R^(5′) represents a C₁–C₃ alkyl group optionally    substituted as defined for R⁵ in formula (I) and R⁶ and R⁷ are as    defined in formula (I), followed by a hydrogenation reaction; or-   (v) when n is 0 and R⁵ represents a C₃–C₅ alkyl group optionally    substituted as defined in formula (I), reacting a compound of    formula (XV), (XVI) or (XVII) as defined in (iv) above, with a    compound of formula

-    wherein R^(5′) is as defined in formula (XVIII) in (iv) above,    followed by a hydrogenation reaction and then an oxidation reaction    and then by reaction with a compound of formula (XIII) as defined    in (i) above under reductive amination conditions; or-   (vi) when n is 1 and X is oxygen or >N—R⁸, reacting a compound of    formula

-    wherein R¹⁷ represents a leaving group (e.g. halogen or    trifluoromethanesulphonate) and m, A, R¹, R² and R³ are as defined    in formula (I), or a compound of formula

-    wherein R¹⁸ represents a leaving group (e.g. halogen or    trifluoromethanesulphonate) and m, A, R¹, R² and R³ are as defined    in formula (I), or a compound of formula

-    wherein R¹⁹ represents a leaving group (e.g. halogen or    trifluoromethanesulphonate) and m, A, R¹, R² and R³ are as defined    in formula (I), with a compound of formula

-    wherein X′ represents oxygen or >N—R⁸ and R⁵, R⁶, R⁷ and R⁸ are as    defined in formula (I); or-   (vii) when A is NHC(O), n is 1 and X is sulphur, reacting a compound    of formula

-    wherein, in each of formulae (XXIV), (XXV) and (XXVI), L⁴    represents a leaving group (e.g. halogen or hydroxyl) and R², R³,    R⁵, R⁶ and R⁷ are as defined in formula (I), with a compound of    formula

-    wherein m and R¹ are as defined in formula (I); or-   (viii) when A is C(O)NH, n is 1 and X is sulphur, reacting a    compound of formula

-    wherein, in each of formulae and (XXVIII), (XXIX) and (XXX), R²,    R³, R⁵, R⁶ and R⁷ are as defined in formula (I), with a compound of    formula

-    wherein L⁵ represents a leaving group (e.g. halogen or hydroxyl)    and m and R¹ are as defined in formula (I); or-   (ix) when n is 0 and R⁵ represents a C₂–C₅ alkyl group substituted    as defined in formula (I), reacting a compound of formula

-    or a compound of formula

-    or a compound of formula

-    wherein, in each of formulae (XXXII), (XXXIII) and (XXXIV), Y    represents a bond or a C₁–C₃ alkyl and m, R¹, R² and R³ are as    defined in formula (I),-    with a compound of formula (XIII) as defined in (i) above, and    optionally thereafter reacting with a C₁–C₆ alkylating agent or with    a halogenating agent; or-   (x) when n is 0 and R⁵ represents a C₃–C₅ alkyl group optionally    substituted as defined in formula (I), reacting a compound of    formula (XV), (XVI) or (XVII) as defined in (iv) above, with a    pre-treated compound of formula

-    in which L⁶ represents a hydrogen atom and R^(5′) represents a    C₁–C₃ alkyl group optionally substituted as defined for R⁵ in    formula (I) and R⁶ and R⁷ are as defined in formula (I), wherein the    compound of formula (XXXV) is pre-treated with a hydroborating    agent; or-   (xi) when n is 0 and R⁵ represents a C₃–C₅ alkyl group optionally    substituted as defined in formula (I), reacting a compound of    formula (XV), (XVI) or (XVII) as defined in (iv) above in the    presence of a suitable catalyst such as    tetrakis(triphenylphosphine)palladium, with a pre-treated compound    of formula

-    in which L⁷ represents a hydrogen atom and R^(5′) represents a    C₁–C₃ alkyl group optionally substituted as defined for R⁵ in    formula (I) and P is a suitable protecting group such as    tert-butyldimethylsilyl, wherein the compound of formula (XXXVIII)    is pre-treated with a hydroborating agent, followed by removal of    the protecting group, P, in a deprotection reaction, then by an    oxidation reaction and then by reaction with a compound of    formula (XIII) as defined in (i) above under reductive amination    conditions; or-   (xii) when n is 0 and R⁵ is (CH₂)₂, reacting a compound of formula    (XV), (XVI) or (XVII) as defined in (iv) above with a compound of    formula

-    wherein R²⁰ represents a suitable leaving group such as    trialkyltin, dialkylboron or zinc, in the presence of a suitable    catalyst such as dichlorobis(triphenylphosphine)palladium, followed    by reaction with a compound of formula (XIII) as defined in (i)    above; or-   (xiii) when n is 0 and R⁵ is CH₂, reacting a compound of formula    (XV), (XVI) or (XVII) as defined in (iv) above with a compound of    formula (XXXIX) as defined in (xii) above, followed by an oxidation    reaction and then by reaction with a compound of formula (XIII) as    defined in (i) above under reductive amination conditions;-   and optionally after (i), (ii), (iii), (iv), (v), (vi), (vii),    (viii), (ix), (x), (xi), (xii) or (xiii) carrying out one or more of    the following:    -   converting the compound obtained to a further compound of        formula (I)    -   forming a pharmaceutically acceptable salt or solvate of the        compound.

In (i) above, the reductive amination is conveniently carried out in thepresence of a reducing agent such as sodium cyanoborohydride,triacetoxyborohydride or sodium borohydride and in a polar solvent suchas methanol, ethanol or dichloromethane either alone or in combinationwith acetic acid.

The base mentioned in (i) is conveniently potassium carbonate and thereaction employing it may be carried out in a polar solvent such asethanol or dimethylformamide.

In process (ii), the alkali metal cyanide used may be sodium orpotassium cyanide. The hydrogenation reaction is conveniently carriedout using hydrogen gas and a hydrogenation catalyst such as Raneynickel.

In process (iii), the reductive amination conditions may be the same asdescribed for (i) above.

In process (iv), the reaction with the acetylenic compound of formula(XVIII) may be carried out in the presence of catalyticbistriphenylphospine dichloride palladium (0), copper (I) iodide and abase (e.g. triethylamine) and in a solvent such as acetonitrile atambient temperature (20° C.). The subsequent hydrogenation reaction mayuse hydrogen gas with a catalyst such as 5% rhodium on carbon in asolvent, for example, ethyl acetate or ethanol, and at a pressure of 3barr.

In process (v), the reaction with the acetylenic compound of formula(XIX) and then the hydrogenation reaction can be performed by proceduresanalogous to those described in the previous paragraph for process (iv).The oxidation reaction can be carried out using standard oxidants (e.g.Dess-Martin periodinane or pyridinium dichromate), in a solvent such asdichloromethane. Reaction with the compound of formula (XIII) is carriedout under reductive amination conditions, for example, in the presenceof a reducing agent such as sodium cyanoborohydride,triacetoxyborohydride or sodium borohydride and in a polar solvent suchas methanol, ethanol or dichloromethane either alone or in combinationwith acetic acid.

Process (vi) may be performed in a solvent such as dimethyl formamide orN-methyl-2-pyrrolidinone, using a base such as caesium carbonate,potassium carbonate or sodium hydride and at elevated temperature, e.g.,≧30° C., more particularly at a temperature in the range from 30 to 150°C., especially 100 to 150° C. A temperature of about 120° C. was foundto be very effective.

Processes (vii) and (viii) are conveniently carried out in a solventsuch as dichloromethane or dimethyl formamide and in the presence ofcarbonyl diimidazole or a coupling agent such as dicyclohexylcarbodiimide.

In process (ix), reaction with the compound of formula (XIII) mayconveniently be carried out in a solvent such asN-methyl-2-pyrrolidinone using a base such as potassium carbonate at atemperature in the range from, for example, 0° C. or 20° C. to 100° C.

Subsequent reaction of the alcohol formed with a C₁–C₆ alkylating agent(e.g. a C₁–C₆ alkyl halide) may be carried out in the same solvent andin the presence of a base such as sodium hydride. Alternatively,subsequent reaction of the alcohol formed with a halogenating agent(e.g. N-bromosuccinimide or N-chlorosuccinimide with triphenylphosphine)may be carried out in a solvent such as tetrahydrofuran.

In process (x), the compound of formula (XXXV) is pre-treated byreaction with a hydroborating reagent (such as9-borabicyclo[3.3.1]nonane or catecholborane) in a solvent (such asdiethyl ether or tetrahydrofuran) at a temperature in the range from 0°C. to 80° C. (in particular from 60° C. to 70° C.) for about 2 to 3hours, then cooling the reaction mixture to room temperature and addinga solution of a base (such as sodium hydroxide in water or tri-potassiumorthophosphate in water) followed by a solution of the compound offormula (XV), (XVI) or (XVII) in a solvent (such as dimethylformamide)and a palladium catalyst (such asdichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II)dichloromethane adduct). The resulting reaction mixture is stirred at atemperature in the range from 25° C. to 90° C. (particularly from 60° C.to 70° C.) for about 2 to 24 hours to yield the desired compounds offormula (I).

In process (xi), the reaction with the vinyl compound of formula(XXXVIII) can be performed by procedures analogous to those outlined inthe paragraph for process (x). With a suitable protecting group, such astert-butyldimethylsilyl, deprotection can be carried out using standardconditions (eg tetra-butylammonium fluoride, hydrofluoric acid) in asolvent such as tetrahydrofuran or water. The subsequent oxidation andreductive amination reactions may be carried out in processes analogousto those outlined in the paragraph for process (v).

In process (xii), the reaction with the vinyl compound of formula(XXXIX) may be carried out in the presence of catalyticdichlorobis(triphenylphosphine)palladium, in a solvent such asN,N-dimethylformamide at an elevated temperature such as 70° C. Thesubsequent addition reaction may be performed under acidic or basicconditions for example in acetic acid in a solvent such as methanol orisopropanol at an elevated temperature such as 100° C.

In process (xiii), the reaction with the vinyl compound of formula(XXXIX) can be performed by procedures analogous to those outlined inthe paragraph for process (xii). The subsequent oxidation can beperformed under standard conditions such as by reaction with ozonefollowed by treatment with dimethylsulfide or triphenylphosphine in asuitable solvent such as dichloromethane or by treatment with osmiumtetroxide and sodium periodate in a suitable solvent such as 1,4-dioxaneand water. The resulting aldehyde can be derivatised by a reductiveamination reaction which may be carried out in a process analogous tothat outlined in the paragraph for process (v).

Compounds of formula (X) in which R¹⁰ represents —C(O)H may be preparedaccording to the following reaction schemes.

(A) is then further reacted as follows.

Compounds of formulae (XI) and (XII) in which R¹¹ and R¹² represent—C(O)H may be prepared in a similar manner to the compounds of formula(X).

Compounds of formula (X) in which R¹⁰ represents —CH₂L¹ and L¹represents, for example, a chlorine atom may be prepared as shown below:

It will be appreciated that compounds of formulae (XI) and (XII) inwhich R¹¹ represents —CH₂L² and R¹² represents —CH₂L³ may be prepared inan analogous manner.

Compounds of formulae (XV), (XVI) and (XVII) may be prepared asdescribed for compound (A) above. Similarly, compounds of formula (XX),(XXI) and (XXII) in which A is NHC(O) may be prepared as described forcompound (A) above. Compounds of formula (XX) in which A is C(O)NH maybe prepared in the following manner:

Compounds of formula (XXI) and (XXII) in which A is C(O)NH may beprepared by analogous processes.

Compounds of formula (XXIV) can be prepared by reacting a compound offormula

wherein L⁷ represents a suitable leaving group such as a halogen atomand R², R³ and L⁴ are as defined in formula (XXIV), with a thiol offormula

in which R⁵, R⁶ and R⁷are as defined in formula (I), in a solvent suchas dimethyl formamide, N-methyl-2-pyrrolidinone or ethanol, in thepresence of a base such as caesium carbonate, potassium carbonate orsodium hydride and at elevated temperature (e.g. 120° C.).

Compounds of formulae (XXV), (XXVI), (XXVIII), (XXIX) and (XXX) may beprepared in a like manner to the compounds of formula (XXIV).

Compounds of formula (XXXII) (and by analogy compounds of formula(XXXIII) and (XXXIV)) can be prepared by the following route:

Compounds of formulae (XIII), (XIV), (XVIII), (XIX), (XXIII), (XXVII),(XXXI), (XXXV), (XXXVI), (XXVII), (XXXVIII) and (XXXIX) are eithercommercially available, are well known in the literature or may beprepared easily using known techniques.

Compounds of formula (I) can be converted into further compounds offormula (I) using standard procedures. For example, compounds of formula(I) in which one of R² and R³ represents a halogen atom may be convertedto a corresponding compound of formula (I) in which one of R² and R³represents a C₁–C₆ alkyl group by reaction with an alkyl Grignardreagent (e.g. methyl magnesium bromide) in the presence of a catalystsuch as [1,3-bis(diphenylphosphino)propane]dichloronickel (II) in asolvent such as tetrahydrofuran.

It will be appreciated by those skilled in the art that in the processesof the present invention certain functional groups such as hydroxyl oramino groups in the starting reagents or intermediate compounds may needto be protected by protecting groups. Thus, the preparation of thecompounds of formula (I) may involve, at various stages, the additionand removal of one or more protecting groups.

The protection and deprotection of functional groups is described in‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 2ndedition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).

The compounds of formula (I) above may be converted to apharmaceutically acceptable salt or solvate thereof, preferably an acidaddition salt such as a hydrochloride, hydrobromide, phosphate, acetate,fumarate, maleate, tartrate, citrate, oxalate, methanesulphonatep-toluenesulphonate, or an alkali metal salt such as a sodium orpotassium salt.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of the compounds offormula (I) and mixtures thereof including racemates. Tautomers andmixtures thereof also form an aspect of the present invention.

The present invention also provides novel intermediates, in particular,intermediates of formula

wherein T represents —C≡C— or —CH₂CH₂—;

-   R³⁰ represents —CHO, —CH₂OP¹ or a group of formula

-   P¹ represents a hydrogen atom or a suitable protecting group (e.g.    t-butyldimethylsilyl);-   P² represents a suitable protecting group (e.g. t-butylcarbamate);-   P³ represents a suitable protecting group (e.g. t-butyldimethylsilyl    or tetrahydro-2H-pyran-2-yl);-   R³¹ represents a C₅–C₅ alkyl group; and-   m, A, R¹, R² and R³ are as defined in formula (I).

In an embodiment of the invention, in formula (IA),

-   m represents 1;-   A represents NHC(O);-   each R¹ represents a hydrogen atom;-   R² represents a halogen atom; and-   R³ represents a hydrogen atom.

The compounds of the present invention are advantageous in that theypossess pharmacological activity. They are therefore indicated aspharmaceuticals for use in the treatment of rheumatoid arthritis,osteoarthritis, psoriasis, allergic dermatitis, asthma, chronicobstructive pulmonary disease (COPD), hyperresponsiveness of the airway,septic shock, glomerulonephritis, inflammatory bowel disease, Crohn'sdisease, ulcerative colitis, atherosclerosis, growth and metastases ofmalignant cells, myoblastic leukaemia, diabetes, Alzheimer's disease,meningitis, osteoporosis, burn injury, ischaemic heart disease, stroke,varicose veins, sarcoidosis, rhinitis, acute and chronic pain, multiplesclerosis, myeloma, bone loss associated with malignancy andinflammatory and neurodegenerative diseases of the eye such asscleritis, episcleritis, uveitis, Sjogrens syndrome-keratoconjuctivitis,sclerokeratitis, optic neuritis, diabetic retinopathy, retinitispigmentosa, antimalarial-induced retinopathy.

Accordingly, the present invention provides a compound of formula (I) ora pharmaceutically acceptable salt or solvate thereof as hereinbeforedefined for use in therapy.

In another aspect, the invention provides the use of a compound offormula (I) or a pharmaceutically acceptable salt or solvate thereof ashereinbefore defined in the manufacture of a medicament for use intherapy.

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

The invention further provides a method of effecting immunosuppression(e.g. in the treatment of rheumatoid arthritis, osteoarthritis,inflammatory bowel disease, atherosclerosis or psoriasis) whichcomprises administering a therapeutically effective amount of a compoundof formula (I) or a pharmaceutically acceptable salt or solvate thereofas hereinbefore defined to a patient.

The invention also provides a method of treating an obstructive airwaysdisease (e.g. asthma or COPD) which comprises administering to a patienta therapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof as hereinbeforedefined to a patient.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated. The daily dosage ofthe compound of formula (I)/salt/solvate (active ingredient) may be inthe range from 0.001 mg/kg to 30 mg/kg.

The compounds of formula (I) and pharmaceutically acceptable salts andsolvates thereof may be used on their own but will generally beadministered in the form of a pharmaceutical composition in which theformula (I) compound/salt/solvate (active ingredient) is in associationwith a pharmaceutically acceptable adjuvant, diluent or carrier.Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% w (percent by weight), morepreferably from 0.10 to 70% w, of active ingredient, and, from 1 to99.95% w, more preferably from 30 to 99.90% w, of a pharmaceuticallyacceptable adjuvant, diluent or carrier, all percentages by weight beingbased on total composition.

Thus, the present invention also provides a pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt or solvate thereof as hereinbefore defined in association with apharmaceutically acceptable adjuvant, diluent or carrier.

The invention further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I) or a pharmaceutically acceptable salt or solvatethereof as hereinbefore defined with a pharmaceutically acceptableadjuvant, diluent or carrier.

The pharmaceutical composition of the invention may be administeredtopically (e.g. to the lung and/or airways or to the skin) in the formof solutions, suspensions, heptafluoroalkane aerosols and dry powderformulations; or systemically, e.g. by oral administration in the formof tablets, capsules, syrups, powders or granules, or by parenteraladministration in the form of solutions or suspensions, or bysubcutaneous administration or by rectal administration in the form ofsuppositories or transdermally.

The present invention will now be further explained by reference to thefollowing illustrative examples. In the examples the NMR spectra weremeasured on a Varian Unity spectrometer at a proton frequency of either300 or 400 MHz. The MS spectra were measured on either a Agilent 1100MSD G1946D spectrometer or a Hewlett Packard HP1100 MSD G1946Aspectrometer. Preparative HPLC separations were performed using a WatersSymmetry® or Xterra® column using 0.1% aqueous trifluoroacetic acid:acetonitrile or 0.1% aqueous airinmoma:acetonitrile as the eluant.

EXAMPLE 1N-(1-Adamantylmethyl)-5-chloro-2-{3-[(3-hydroxypropyl)-amino]propyl}isonicotinamide

(i) 2-Bromo-5-chloro isonicotinic acid

To a stirred solution of di-isopropylamine (16 ml) in anhydroustetrahydrofuran (300 ml) at −5° C. was added, dropwise a solution ofn-butyl lithium in hexane (2.5 molar, 44 ml) and the resulting solutionwas stirred for 30 minutes and was then cooled to −70° C. To the cooledsolution was added a solution of 2-bromo-5-chloropyridine (19.2 g) inanhydrous tetrahydrofaran (50 ml) maintaining the internal temperatureof the reaction below −65° C. The reaction was maintained at −70° C. for15 minutes and then a steady stream of dried carbon dioxide was passedthrough the reaction mixture for 30 minutes. The reaction was allowed towarm to room temperature and was poured into a mixture of water (300 ml)and aqueous sodium hydroxide solution (2M, 30 ml). The mixture wasextracted with ether and (2×100 ml) and the combined ethereal extractswere back extracted with aqueous sodium hydroxide solution (1M, 2×100ml). The combined aqueous extracts were acidified to pH 1 withconcentrated hydrochloric acid and the resulting solid filtered anddried under vacuum at 50° C. to afford the sub-titled compound as awhite solid (14.1 g).

¹H NMR (300 MHz, DMSO-d₆) δ 8.63 (1H, s); 7.98 (1H, s) MP: 246–247° C.(dec.)

(ii) N-(1-Adamantylmethyl)-2-bromo-5-chloroisonicotinamide

To a stirred suspension of 2-bromo-5-chloro isonicotinic acid (5.0 g) inanhydrous dichloromethane (30 ml) was added dimethylformamide (1 drop)followed by oxalyl chloride (3.7 ml). The reaction was stirred at roomtemperature for 2 hours and was then evaporated to dryness, azeotropingwith toluene. The residue was suspended in ethyl acetate (100 ml) andwas cooled to 5° C. where a solution of 1-adamantylmethylamine (3.47 g)and triethylamine (7.0 ml) in ethyl acetate (10 ml) was added dropwise.The mixture was stirred for 2 hours and was then poured into water andthe resulting solid filtered and dried under vacuum at 40° C. to affordthe titled compound as a white solid (8.05 g).

¹H NMR (400 MHz, CDCl₃) δ 8.42 (1H, s); 7.77 (1H, s); 6.24 (1H, t); 3.16(2H, dd); 2.05–2.02 (3H, m); 1.76–1.73 (3H, m); 1.66–1.63 (3H, m);1.57–1.55 (6H, m). MP: 153–155° C. (dec.) MS: APCI(+ve) 383/385 (M+1)

(iii)N-(1-Adamantylmethyl)-5-chloro-2-(3-hydroxy-1-propynyl)isonicotinamide

A mixture of N-(1-adamantylmethyl)-2-bromo-5-chloroisonicotinamide(Example 1(ii)) (0.96 g), propargyl alcohol (0.16 g), copper (I) iodide,bis-triphenylphosphine palladium is dichloride (0.035 g) anddiethylamine (10 ml) was stirred together at room temperature for 20hours. The mixture was concentrated and the residue partitioned betweenethyl acetate and 1M aqueous hydrochloric acid solution (2×25 ml) andthe mixture was extracted into ethyl acetate (3×25 ml). The combinedextracts were dried over anhydrous magnesium sulfate, filtered andconcentrated. The residue was purified by chromatography on silica geleluting with ethyl acetate:iso-hexane (1:4 to 1:1) and then ethylacetate to afford the sub-titled compound (0.48 g) as an oil.

¹H NMR (400 MHz, CDCl₃) δ 8.59 (1H, s); 7.69 (1H, s); 6.30 (1H, t); 4.52(2H, d); 3.18 (2H, d); 2.05–2.02 (3H, m); 1.87 (1H, t); 1.76–1.73 (3H,m); 1.66–1.63 (3H, m); 1.57–1.55 (6H, m). MS: APCI(+ve) 359/361 (M+1)

(iv) N-(1-Adamantylmethyl)-5-chloro-2-(3-hydroxypropyl)isonicotinamide

A stirred suspension ofN-(1-adamantylmethyl)-5-chloro-2-(3-hydroxy-1-propynyl)isonicotinamide(Example 1 (iii)) (0.48 g) and 5% rhodium on carbon (0.020 g) wasstirred under a positive pressure (3 barr) of hydrogen until no furtheruptake was observed. The mixture was filtered and concentrated. Theresidue was purified by chromatography on silica gel eluting with ethylacetate to afford the sub-titled compound (0.305 g) as an oil.

¹H NMR (300 MHz, CDCl₃) δ 8.54 (1H, s); 7.50 (1H, s); 6.34 (1H, t); 3.69(2H, dd); 3.18 (2H, d); 2.96 (2H, t); 2.62 (1H, t); 2.05–2.02 (5H, m);1.76–1.73 (3H, m); 1.66–1.63 (3H, m); 1.57–1.55 (6H, m). MS: APCI(+ve)363/365 (M+1)

(v)N-(1-Adamantylmethyl)-5-chloro-2-{3-[(3-hydroxypropyl)-amino]propyl}isonicotinamide

To a stirred solution ofN-(1-adamantylmethyl)-5-chloro-2-(3-hydroxypropyl)isonicotinamide(Example 1(iv)) (0.30 g) in dry dichloromethane (20 ml) was addedDess-Martin periodinane (0.42 g) and the resulting suspension stirred atroom temperature for 30 minutes. The reaction was poured into a mixtureof saturated sodium bicarbonate solution containing sodium thiosulfate(10% w/v, 20 ml) and the mixture was extracted into ethyl acetate (3×25ml). The combined extracts were dried over anhydrous magnesium sulfate,filtered and concentrated. The crude aldehyde was dissolved in methanol(2 ml) and 3-aminopropan-1-ol (0.15 g) added along with acetic acid (0.1ml). The mixture was stirred for 2 hours at ambient temperature and thensodium triacetoxy borohydride (0.424 g) was added and the reactionstirred for 20 hours, concentrated and the residue was partitionedbetween 2M aqueous hydrochloric acid solution (10 ml) and ethyl acetate(10 ml). The layers were separated and the organic phase re-extractedwith 2N hydrochloric acid (2×10 ml). The combined aqueous extracts werebasified with 5M aqueous ammonium hydroxide solution, extracted intoethyl acetate (2×25 ml) and the combined extracts were dried overanhydrous magnesium sulfate, filtered and concentrated. The residue waspurified by chromatography on silica gel eluting with 0.7N anhydrousammonia in methanol:dichloromethane (1:4) to afford the titled compound(0.116 g) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 8.54 (1H, s); 7.34 (1H, s); 6.97 (1H, t); 3.74(2H, t); 3.15 (2H, d); 2.87–2.81 (4H, m); 2.66 (2H, t); 2.05–1.96 (5H,m); 1.76–1.73 (3H, m; 1.66–1.63 (5H, m); 1.57–1.55 (6H, m). MS:APCI(+ve) 420/422 (M+1) MP: 84–85° C.

EXAMPLE 2N-(1-Adamantylmethyl)-5-chloro-2-{3-[(3-hydroxypropyl)amino]propyl}-isonicotinamidedihydrochloride

Preparative Route 1 (i)N(1-Adamantylmethyl)-2-bromo-5-chloroisonicotinamide

To a stirred solution of di-isopropylamine (2.1 ml) in anhydroustetrahydrofuran (15 ml) at is −5° C. was added, dropwise a solution ofn-butyl lithium in hexane (2.5 molar, 4.8 ml) and the resulting solutionwas stirred for 30 minutes and was then cooled to −70° C. To the cooledsolution was added a solution of 2-bromo-5-chloropyridine (2.39 g) inanhydrous tetrahydrofuran (10 ml) maintaining the internal temperatureof the reaction below −65° C. The reaction was maintained at −70° C. for15 minutes and then a solution of 1-adamantylmethyl isocyanate (1.91 g)in anhydrous tetrahydrofuran (5 ml) was dropwise added (care exotherm).The mixture was stirred for 10 minutes and was then poured into asolution of 1M aqueous hydrochloric acid solution (50 ml) and themixture extracted into ethyl acetate (3×25 ml). The combined extractswere dried over anhydrous magnesium sulfate, filtered and concentrated.The residue was purified by chromatography on silica gel eluting withethyl acetate:iso-hexane (1:9 to 1:4 to 1:1) to afford the sub-titledcompound (2.70 g) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 8.41 (1H, s); 7.98 (1H, s); 6.21 (1H, t); 3.16(2H, d); 2.05–2.02 (3H, m); 1.76–1.73 (3H, m); 1.66–1.63 (3H, m);1.57–1.55 (6H, m). MP: 193–194° C.

(ii) tert-Butylprop-2-ynyl[3-(tetrahydro-2H-pyran-2-yloxy)propyl]carbamate

A solution of tert-butyl prop-2-ynylcarbamate (1.2 g) in anhydrousN,N-dimethylformamide (5 ml) was treated with 60% sodium hydride (0.245g) in one portion. After evolution of hydrogen had ceased2-(3-bromopropoxy)tetrahydro-2H-pyran (1.36 g) was added. The reactionmixture was stirred under nitrogen for 48 hours then diluted with water(50 ml) and extracted into ethyl acetate (3×25 ml). The combinedextracts were dried over anhydrous sodium sulphate, filtered andconcentrated to afford the sub-titled compound (1.61 g) as a colourlessoil.

¹H NMR (400 MHz, CDCl₃) δ 4.60 (2H, m); 4.05 (2H, broad); 3.90–3.70 (4H,m); 3.60–3.41 (7H, m); 2.22–2.09 (3H, m); 1.91–1.82 (4H, m); 1.47 (9H,s).

(iii) tert-Butyl3-(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)prop-2-ynyl[3-(tetrahydro-2H-pyran-2-yloxy)propyl]carbamate

A suspension of N-(1-adamantylmethyl)-2-bromo-5-chloroisonicotinamide(Example 2(i)) (0.43 g) and tert-butylprop-2-ynyl[3-(tetrahydro-2H-pyran-2-yloxy)propyl]carbamate (Example2(ii)) (0.60 g) in anhydrous acetonitrile (6 ml) and triethylamine (6ml) was purged with nitrogen for 5 minutes and then copper (I) iodide(0.004 g) and bis-triphenyphosphine palladium dichloride (0.014 g) wereadded. The mixture was stirred under nitrogen for 2 hours. The mixturewas concentrated and the residue was purified by chromatography onsilica gel eluting with iso-hexane:ethyl acetate (19:1 to 7:3) to affordthe sub-titled compound (0.39 g) as a yellow gum.

¹H NMR (400 MHz, CDCl₃) δ 8.58 (1H, s); 7.67 (1H, s); 6.25 (1H, broad);4.57 (1H, t); 4.33 (2H, broad); 3.9–3.77 (2H, m); 3.5–3.41 (4H, m); 3.18(2H, d); 2.02 (3H, broad); 1.92–1.85 (2H, t); 1.80–1.60 (7H, m); 1.58(12H, s); 1.48 (9H, s). MS: APCI(+ve) 516/518

(iv) tert-Butyl3-(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)propyl[3-(tetrahydro-2H-pyran-2-yloxy)propyl]carbamate

A stirred suspension of tert-butyl3-(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)prop-2-ynyl[3-(tetrahydro-2H-pyran-2-yloxy)propyl]carbamate(Example 2(iii)) (0.35 g) and 5% rhodium on carbon (0.020 g) was stirredunder a positive pressure (2 barr) of hydrogen until no further uptakewas observed. The mixture was filtered and concentrated. The residue waspurified by chromatography on silica gel eluting withdichloromethane:acetone (19:1 to 9:1) to afford the sub-titled compound(0.24 g) as a colourless gum.

¹H NMR (300 MHz, CDCl₃) δ 8.54 (1H, s); 7.44 (1H, s); 6.42 (1H, broad);4.54 (1H, t); 3.83 (1H, t of d); 3.73 (1H, m); 3.50 (1H, m); 3.38 (1H,m); 3.25 (4H, t); 3.19 (2H, d); 2.78 (2H, t); 2.01–1.9 (5H, m); 1.80(2H, t); 1.78–1.62 (4H, d of d), 1.60 (10H, d); 1.44 (9H, s). MS:APCI(+ve) 604/606 (M+1)

(v)N-(1-Adamantylmethyl)-5-chloro-2-{3-[(3-hydroxypropyl)amino]propyl}-isonicotinamidedihydrochloride

tert-Butyl3-(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)propyl[3-(tetrahydro-2H-pyran-2-yloxy)propyl]carbamate(Example 2(iv)) (0.24 g) was dissolved in a mixture of methanol (10 ml)and 2M aqueous hydrochloric acid solution (10 ml); the solution was leftto stand for 0.5 hours. The mixture was concentrated and the residuediluted with 2M aqueous sodium hydroxide solution (25 ml). The mixturewas extracted into dichloromethane (3×25 ml) and the combined extractswere concentrated. The residue was dissolved in a solution of hydrogenchloride in 1,4-dioxane (10 ml of a 4M solution) and left to stand for0.5 hours. The solution was concentrated and the residue suspended in 2Maqueous sodium hydroxide solution (25 ml), extracted intodichloromethane (3×25 ml) and the combined extracts were concentrated.The residue was purified by chromatography on silica gel eluting withdichloromethane:methanol:0.88 aqueous ammonia (89:10:1). The isolatedmaterial was dissolved in a solution of hydrogen chloride in 1,4-dioxane(10 ml of a 4M solution) and concentrated; the resultant solid wasrecrystallised from ethyl acetate/methanol to afford the titled compound(0.115 g) as a colourless solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (2H, broad); 8.60 (1H, s); 8.54 (1H,t); 7.36 (1H, s); 3.46 (2H, t); 2.95–2.83 (8H, m); 2.08–1.99 (2H, q);1.95 (3H, s); 1.81–1.74 (2H, t); 1.69–1.58 (6H, q); 1.52 (6H, s). MS:APCI(+ve) 420/422 (M+1) MP: decomposed at 210° C.

Preparative Route 2 (vi)tert-Butyl[3-(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)propyl](3-{[tert-butyl(dimethyl)silyl]oxy}propyl)carbamate

A solution of tert-butylallyl(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)carbamate (0.50 g) in9-boroabicyclo[3.3.1]nonane (6.0 ml of a 0.5M solution intetrahydrofuran) was heated at reflux under nitrogen for 4 hours. Thesolution was cooled to 0° C. and potassium phosphate (2 ml of a 3Msolution in water) was added. The mixture was stirred for 15 minutes anda solution of N-(1-adamantylmethyl)-2,5-dichloroisonicotinamide (0.50 g)(prepared as described in WO 01/94338) andtetrakis(triphenylphosphine)palladium (0) (0.045 g) in anhydrousN,N-dimethylformamide (3 ml) was added. The mixture was heated at 70° C.under nitrogen for 4 hours, diluted with saturated brine (25 ml) andextracted into ethyl acetate (3×25 ml). The combined extracts were driedover anhydrous sodium sulphate, filtered and concentrated. The residuewas purified by chromatography on silica, gel eluting withiso-hexane:ethyl acetate (9:1 to 4:1) to afford the sub-titled compound(0.46 g).

MS: APCI(+ve) 636/634 (M+1)

(vii)N-(1-Adamantylmethyl)-5-chloro-2-{3-[(3-hydroxypropyl)amino]propyl}isonicotinamidedihydrochloride

tert-Butyl[3-(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)propyl](3-{[tert-butyl(dimethyl)silyl]oxy}propyl)carbamate(Example 2(vi)) (0.46 g) was dissolved in a solution of hydrogenchloride in 1,4-dioxane (10 ml of a 4M solution) and concentrated; theresultant solid was recrystallised from 1,4-dioxane/methanol and thesolid collected by filtration to afford the titled compound (0.24 g) asa colourless powder.

¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (2H, broad); 8.60 (1H, s); 8.54 (1H,t); 7.36 (1H, s); 3.46 (2H, t); 2.95–2.83 (8H, m); 2.08–1.99 (2H, q);1.95 (3H, s); 1.81–1.74 (2H, t); 1.69–1.58 (6H, q); 1.52 (6H, s). MS:APCI(+ve) 420/422 (M+1) MP: decomposed at 210° C.

EXAMPLE 3N-(1-Adamantylmethyl)-2-chloro-5-{3-[(3-hydroxypropyl)amino]propyl}nicotinamide

(i) N-(1-Adamantylmethyl)-5-iodo-2-chloronicotinamide

2-Hydroxy-5-iodo-nicotinic acid (2.65 g) was added to thionyl chloride(10 ml) followed by anhydrous N,N-dimethylformamide (1 drop) and theresulting suspension heated to 100° C. for 3 hours. The mixture wascooled and concentrated, azeotroping with toluene. The residue wasdissolved in dry dichloromethane (70 ml), cooled to 0° C. and a mixtureof 1-adamantylmethylamine (1.65 g) and triethylamine (2.81 ml) in drydichloromethane (30 ml) added dropwise. The reaction mixture was stirredfor 1 hour, was washed with 0.5M aqueous hydrochloric acid, dried overanhydrous magnesium sulfate, filtered and concentrated. The residue waspurified by chromatography on silica gel eluting with ethylacetate:dichloromethane (1:9) to afford the sub-titled compound as asolid.

¹H NMR (300 MHz, CDCl₃) δ 8.65 (1H, d); 8.42 (1H, d); 6.50 (1H, t); 3.19(2H, dd); 2.05–2.02 (3H, m); 1.76–1.73 (3H, m); 1.66–1.63 (3H, m);1.57–1.55 (6H, m). MS: APCI(+ve) 430/432 (M+1) MP: 163–164° C.

(ii) N-(1-Adamantylmethyl)-2-chloro-5-(3-oxopropyl)nicotinamide

A mixture of N-(1-adamantylmethyl)-5-iodo-2-chloronicotinamide (Example3(i)) (2.15 g), allyl alcohol (0.58 g), palladium (II) acetate (0.015g), sodium bicarbonate (1.05 g) and tetra-butyl ammonium chloride (1.39g) were stirred together in anhydrous N,N-dimethylformamide (20 ml) for20 hours. The reaction mixture was poured into water (100 ml) andextracted into ethyl acetate (3×25 ml). The combined extracts were driedover anhydrous magnesium sulfate, filtered and concentrated. The residuewas purified by chromatography on silica gel eluting with ethylacetate:iso-hexane (1:1) to afford the sub-titled compound (0.65 g).

¹H NMR (300 MHz, CDCl₃) δ 9.82 (1H, s); 8.33 (1H, d); 8.01 (1H, d); 6.50(1H, t); 3.19 (2H, d); 2.98 (2H, dd); 2.86 (2H, dd); 2.05–2.02 (3H, m);1.76–1.73 (3H, m); 1.66–1.63 (3H, m); 1.57–1.55 (6H, m). MS: APCI(+ve)361, 363 (M+1)

(iii)N-(1-Adamantylmethyl)-2-chloro-5-{3-[(3-hydroxypropyl)amino]propyl}-nicotinamide

To a stirred solution ofN-(1-adamantylmethyl)-2-chloro-5-(3-oxopropyl)nicotinamide (Example3(ii)) (0.10 g) in methanol (3 ml) and acetic acid (0.1 ml) was added.3-aminopropanol (0.042 g) and the resulting solution was stirred for 2hours and then sodium cyanoborohydride (0.020 g) was added and thereaction mixture stirred for 20 hours. The mixture was concentrated andthe residue partitioned between 2M aqueous hydrochloric acid solutionand ethyl acetate (2×10 ml). The layers were separated and the organicphase re-extracted with ²M aqueous hydrochloric acid solution (2×10 ml).The combined aqueous extracts were basified with 5M aqueous ammoniumhydroxide solution, extracted into ethyl acetate (2×25 ml) and thecombined extracts were dried over anhydrous magnesium sulfate, filteredand concentrated to afford the titled compound (0.075 g) as a whitesolid.

¹H NMR (400 MHz, CDCl₃) δ 8.28 (1H, s); 7.93 (1H, s); 6.79 (1H, t); 3.79(2H, t); 3.17 (2H, d); 2.86 (2H, t); 2.71 (2H, t); 2.65 (2H, t); 2.66(2H, t); 2.05–1.96 (5H, m); 1.87–1.80 (2H, m); 1.76–1.73 (3H, m)1.66–1.63 (3H, m); 1.57–1.55 (6H, m). MS: APCI(+ve) 420/422 (M+1) MP:105–107° C.

EXAMPLE 4N-(1-Adamantylmethyl)-2-chloro-5-(3-{[(1S)-2-hydroxy-1-methylethyl]amino}propyl)nicotinamide

The titled compound was prepared fromN-(1-adamantylmethyl)-2-chloro-5-(3-oxopropyl)nicotinamide (Example3(ii) (0.10 g), (S)-2-aminopropanol (0.046 g) and sodiumcyanoborohydride 0.020 g) in methanol (3 ml) and acetic acid (0.1 ml) bythe method of Example 3(iii). The crude product was purified bychromatography on silica gel eluting with 0.7N anhydrous ammonia inmethanol:ethyl acetate (1:5) to afford the titled compound as an oil(0.082 g).

¹H NMR (300 MHz, CDCl₃) δ 8.28 (1H, s); 7.99 (1H, s); 6.64 (1H, t); 3.56(2H, dd); 3.23 (2H, dd); 3.19 (2H, d); 2.80–2.70 (3H, m); 2.58–2.50 (1H,m); 2.05–1.96 (3H, m); 1.87–1.80 (2H, m); 1.76–1.73 (3H, m); 1.66–1.63(3H, m); 1.57–1.55 (6H, m); 1.04 (3H, d). MS: APCI(+ve) 420/422 (M+1)

EXAMPLE 5N-(1-Adamantylmethyl)-2-chloro-5-(3-{[(1R)-2-hydroxy-1-methylethyl]amino}propyl)nicotinamide

The titled compound was prepared fromN-(1-adamantylmethyl)-2-chloro-5-(3-oxopropyl)nicotinamide (Example3(ii)) (0.10 g), (R)-2-aminopropanol (0.046 g) and sodiumcyanoborohydride (0.020 g) in methanol (3 ml) and acetic acid (0.1 ml)by the method of Example 3(iii). The product was purified bychromatography on silica gel eluting with 0.7M anhydrous ammonia inmethanol:ethyl acetate (1:5) to afford the titled compound as an oil(0.085 g).

¹H NMR (300 MHz, CDCl₃) δ 8.28 (1H, s); 7.99 (1H, s); 6.64 (1H, t); 3.56(2H, dd); 3.23 (2H, dd); 3.19 (2H, d); 2.80–2.70 (3H, m); 2.58–2.50 (1H,m); 2.05–1.96 (3H, m); 1.87–1.80 (2H, m); 1.76–1.73 (3H, m); 1.66–1.63(3H, m); 1.57–1.55 (6H, m); 1.04 (3H, d). MS: APCI(+ve) 420/422 (M+1)

EXAMPLE 6N-(1-Adamantylmethyl)-2-(3-aminopropyl)-5-chloroisonicotinamidehydrochloride

(i) tert-Butyl3-(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)prop-2-ynylcarbamate.

A suspension of N-(1-adamantylmethyl)-5-chloro-2-iodoisonicotinamide(Example2(i)) (0.43 g) and tert-butyl prop-2-ynylcarbamate, (0.31 g) inanhydrous acetonitrile (5 ml) and triethylamine (5 ml) was purged withnitrogen for 5 minutes and the copper (I) iodide (0.004 g) andbis-triphenyphosphine palladium dichloride (0.014 g) were added. Themixture was stirred under nitrogen for 0.75 hours. The mixture wasconcentrated and the residue was purified by chromatography on silicagel eluting with acetone:dichloromethane (1:19) to afford the sub-titledcompound (0.34 g) as a yellow foam.

¹H NMR (400 MHz, CDCl₃) δ 8.58 (1H, s); 7.67 (1H, s); 6.25 (1H, t); 4.82(1H, broad); 4.18 (2H, d); 3.18 (2H, d); 2.02 (3H, s); 1.76–1.64 (4H, dof d); 1.60–1.57 (10H, d); 1.46 (9H, s). MS: APCI(+ve) 458/460 (M+1)

(ii) N-(1-Adamantylmethyl)-2-(3-aminopropyl)-5-chloroisonicotinamidehydrochloride

A stirred suspension of tert-butyl3-(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)prop-2-ynylcarbamate(Example 6(i)) (0.34 g) and 5% rhodium on carbon was stirred under apositive pressure (2 barr) of hydrogen until no further uptake wasobserved. The mixture was filtered and concentrated. The residue wasdissolved in a solution of hydrogen chloride in 1,4-dioxane (10 ml of a4M solution) and left to stand for 0.5 hours. The solution wasconcentrated and the residue triturated with ethyl acetate to afford thetitled compound (0.174 g) as a beige powder.

¹H NMR (300 MHz, DMSO-d₆) δ 8.60 (1H, s); 8.54 (1H, t); 8.02 (3H,broad); 7.34 (1H, s); 2.94 (2H, d); 2.85 (4H, m); 1.97 (5H, m); 1.7–1.58(6H, q); 1.52 (6H, s). MS: APCI(+ve) 362/364 (M+1) MP: 150° C. (dec.)

EXAMPLE 7N-(1-Adamantylmethyl)-5-chloro-2-[3-(ethylamino)propyl]isonicotinamidehydrochloride

Preparative Route 1 (i) tert-Butyl ethyl(prop-2-ynyl)carbamate

The sub-titled compound was prepared from tert-butylprop-2-ynylcarbamate (0.6g), 60% sodium hydride (0.186 g), ethyl iodide(1.55 ml) and anhydrous N-methyl-2-pyrrolidinone (4 ml) by the method ofExample 2(ii). The crude product was purified by chromatography onsilica gel eluting with iso-hexane:ethyl acetate (19:1) to afford (0.34g) of a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 4.04 (2H, broad); 3.36 (2H, q); 2.18 (1H, t);1.14 (3H, t); 1.47 (9H, s).

(ii) tert-Butyl3-(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin2-yl)prop-2-ynyl(ethyl)carbamate

The sub-titled compound was prepared from N-(1adamantylmethyl)-5-chloro-2-iodoisonicotinamide (Example 2(i)) (0.40 g),tert-butyl ethyl(prop-2-ynyl)carbamate (Example 7(i)) (0.34 g), copper(I) iodide (0.004 g), bis-triphenyphosphine palladium dichloride (0.014g), triethylamine (5 ml) and anhydrous acetonitrile (5 ml) by the methodof Example 2(iii). The crude product was purified by chromatography onsilica gel eluting with iso-hexane:ethyl acetate (9:1 to 7:3) to affordthe sub-titled compound (0.30 g).

¹H NMR (400 MHz CDCl₃) δ 8.58. (1H, s); 7.67 (1H, s); 6.22 (1H, broad);4.31 (2H, broad); 3.42 (2H, q); 3.18 (2H, d); 2.02 (3H, broad);1.80–1.60 (6H, d of d); 1.57 (6H, s); 1.48 (9H, s); 1.18(3H, t). MS:APCI(+ve) 486/488 (M+1)

(iii)N-(1-Adamantylmethyl)-5-chloro-2-[3-(ethylamino)propyl]isonicotinamidehydrochloride

The titled compound was prepared from tert-butyl3-(4-{[(1-adamantylmethyl)amino]-carbonyl}-5-chloropyridin-2-yl)prop-2-ynyl(ethyl)carbamate(Example 7(ii)) (0.30 g) by the method of Example 6(ii). The crudehydrochloride salt was suspended in 2M aqueous sodium hydroxide solution(25 ml), extracted into ethyl acetate (3×25 ml). and the combinedextracts were concentrated. The residue was purified by chromatographyon silica gel eluting with dichloromethane:methanol:0.88 aqueous ammonia(89:10:1). The isolated material was dissolved in a solution of hydrogenchloride in 1,4-dioxane (10 ml of a 4M solution) and concentrated; theresultant solid was triturated with ethyl acetate and the solidcollected by filtration. Final purification was by preparative reversephase HPLC to afford the titled compound (0.025 g) as a colourlesspowder.

¹H NMR (300 MHz, DMSO-d₆) δ 8.84 (2H, broad); 8.61 (1H, s); 8.54 (1H,t); 7.36 (1H, s); 3.0–2.80 (8H, m); 2.04 (2H, q); 1.95 (3H, s); 1.7–1.58(6H, q); 1.52 (6H, s); 1.19 (3H, t). MS: APCI(+ve) 390/392 (M+1) MP:206–208° C. (dec.)

Preparative Route 2 (iv) tert-Butyl allyl(ethyl)carbamate

The sub-titled compound was prepared from tert-butyl allylcarbamate (1.0g), 60% sodium hydride (0.254 g), ethyl iodide (1.55 ml) and anhydrousN-methyl-2-pyrrolidinone (4 ml) by the method of Example 2(ii). Thecrude product was purified by chromatography on silica gel eluting withiso-hexane:ethyl acetate (19:1) to afford (0.53 g) of a colourless oil.

¹H NMR (400 MHz, CDCl₃) δ 5.78 (1H, m); 5.12 (2H, m), 3.80 (2H, s); 3.22(2H, d); 1.46 (9H, s); 1.08 (3H, t).

(v)N-(1-Adamantylmethyl)-5-chloro-2-[3-(ethylamino)propyl]isonicotinamidehydrochloride

A solution of tert-butyl allylcarbamate (Example 7(iv)) (0.23 g) in9-boroabicyclo[3.3.1]nonane (5 ml of a 0.5M solution in tetrahydrofuran)was heated at reflux under nitrogen for 6 hours. The solution was cooledto room temperature and potassium phosphate (1 ml of a 3M solution inwater) was added. The mixture was stirred for 15 minutes and a solutionof N-(1-adamantylmethyl)-2-bromo-5-chloroisonicotinamide (Example 1(ii))(0.383 g) and dichloro[1,1′-bis(diphenylphosphino)ferrocenyl]palladium(II) (0.045 g) in anhydrous N,N-dimethylformamide (8 ml) was added. Themixture was stirred for 6 hours, diluted with saturated brine (25 ml)and extracted into ethyl acetate (3×25 ml). The combined extracts weredried over anhydrous sodium sulphate, filtered and concentrated. Theresidue was purified by chromatography on silica gel eluting withiso-hexane:ethyl acetate (4:1 to 2:1). The isolated material (0.30 g)was dissolved in a solution of hydrogen chloride in 1,4-dioxane (10 mlof a 4M solution) and concentrated; the resultant solid was trituratedwith ethyl acetate and the solid collected by filtration to afford thetitled compound (0.245 g) as a colourless powder.

EXAMPLE 8N-(1-Adamantylmethyl)-5-chloro-2-({2-[(3-hydroxypropyl)amino]-ethyl}thio)isonicotinamidehydrochloride

(i) 2-({2-[(tert-Butoxycarbonyl)amino]ethyl}thio)-5-chloroisonicotinicacid

To a solution of 2,5-dichloroisonicotinic acid (1.82 g) in anhydrousN,N-dimethylformamide (10 ml) was added 60% sodium hydride (0.455 g) insmall portions. After gas evolution had ceased tert-butyl2-mercaptoethylcarbamate (1.60 ml) was added. The reaction mixture wasthen heated at 60° C. under nitrogen for 10 hours. Further amounts of60% sodium hydride (0.225 g) and tert-butyl 2-mercaptoethylcarbamate(1.60 ml) were then added and heating was continued for 2 hours. Thereaction mixture was concentrated and the residue suspended in 2Maqueous hydrochloric acid (25 ml) and extracted into ethyl acetate (3×25ml). The combined extracts were dried over anhydrous sodium sulphate,filtered and concentrated. The residue was purified by chromatography onsilica gel eluting with iso-hexane:ethyl acetate:acetic acid (6:4:0.1)to afford the sub-titled compound (1.0 g) as a colourless powder.

¹H NMR (300 MHz, DMSO-d₆) δ 8.59 (1H, s); 7.60(1H, s); 7.02 (1H, s);3.20 (4H, s); 1.37 (9H, s).

(ii) tert-Butyl2-[(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)thio]ethyl[3-(tetrahydro-2H-pyran-2-yloxy)propyl]carbamate

To a solution of2-({2-[(tert-butoxycarbonyl)amino]ethyl}thio)-5-chloroisonicotinic acid(Example 8(i)) (0.332 g) in anhydrous N-methyl-2-pyrrolidinone (5 ml)was added 60% sodium hydride (0.084 g). After 0.5 hours2-(3-bromopropoxy)tetrahydro-2H-pyran (0.244 g) was added and themixture was stirred for 16 hours under nitrogen. The reaction mixturewas diluted with water (50 ml) and ethyl acetate (50 ml) followed by 2Maqueous hydrochloric acid solution (50 ml). The mixture was extractedinto ethyl acetate (3×25 ml) and the combined extracts were dried overanhydrous sodium sulphate, filtered and concentrated. The residue wasdissolved in anhydrous N,N-dimethylformamide (5 ml) and1,1′-carbonyldiimidazole (0.162 g) was added. After 3 hours the mixturewas treated with 1-adamantylmethylamine (0.163 g) in one portion and thewhole was stirred for 72 hours. The reaction mixture was diluted withwater (50 ml) and extracted into ethyl acetate (3×25 ml); the combinedextracts were dried over anhydrous sodium sulphate, filtered andconcentrated. The residue was purified by chromatography on silica geleluting with dichloromethane:ethyl acetate (9:1) to afford thesub-titled compound (0.15 g) as a colourless oil.

MS: APCI(+ve) 622/624 (M+1).

(iii)N-(1-Adamantylmethyl)-5-chloro-2-({2-[(3-hydroxypropyl)amino]ethyl}-thio)isonicotinamidehydrochloride

The titled compound was prepared from tert-butyl2-[(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)thio]ethyl[3-(tetrahydro-2H-pyran-2-yloxy)propyl]carbamate(Example 8(ii)) (0.15 g) by the method of Example 2(v). The crudehydrochloride salt was triturated with ethyl acetate to afford thetitled compound (0.084 g) as a colourless foam.

¹H NMR (300 MHz, DMSO-d₆) δ 8.81 (1H, broad); 8.57 (1H, s); 8.54 (1H,t); 7.44 (1H, s); 3.50–3.42 (4H, m); 3.19 (2H, t); 3.01 (2H, t); 2.93(2H, d); 1.94 (3H, s); 1.76 (2H, quintet); 1.69–1.57 (6H, q); 1.51 (6H,s). MS: APCI(+ve) 438/440 (M+1).

EXAMPLE 9N-(1-Adamantylmethyl)-5-chloro-2-(3-{[(1R)-2-hydroxy-1-methylethyl]amino}propyl)isonicotinamide,dihydrochloride

By the method outlined for Example 1(v) and using(R)-2-amino-1-propanol, the compoundN-(1-adamantylmethyl)-5-chloro-2-(3-{[(1R)-2-hydroxy-1-methylethyl]amino}propyl)isonicotinamidewas afforded as an oil.

¹H NMR (300 MHz, CDCl₃) δ 8.55 (1H, s); 7.45 (1H, s); 6.47 (1H, t); 3.53(1H, dd); 3.21–3.16 (3H, m); 2.88 (2H, t); 2.81–2.69 (2H, m); 2.56–2.48(1H, m); 2.05–1.96 (3H, m); 1.96–1.88 (2H, m); 1.76–1.63 (6H, m);1.57–1.55 (6H, m); 1.03 (3H, d). MS: APCI(+ve) 420/422 (M+1)

The compound from above (0.100 g) was dissolved in dry hydrogen chloridein 1,4-dioxane (4N, 2 ml) and was concentrated. The residue wasrecrystallised from methanol:ethyl acetate to afford the titled compound(0.095 g) as a solid.

¹H NMR (300 MHz, DMSO-d₆) δ 8.62 (2H, br); 8.60 (1H, s); 8.53 (1H, t);7.35 (1H, s); 3.65 (1H, dd); 3.47 (1H, dd); 3.22 (1H, br); 2.94 (2H, d);2.85 (2H, t); 2.04 (2H, p); 1.98–1.96 (3H, m); 1.76–1.63 (6H, m);1.57–1.55 (6H, m); 1.18 (3H, d). MS: APCI(+ve) 420/422 (M+1) MP:205–208° C.

EXAMPLE 10N-(1-Adamantylmethyl)-5-chloro-2-(3-{[(1S)-2-hydroxy-1-methylethyl]amino}propyl)isonicotinamide,dihydrochloride

By the method outlined for Example 1(v) and using(S)-2-amino-1-propanol, the compoundN-(1-adamantylmethyl)-5-chloro-2-(3-{[(1S)-2-hydroxy-1-methylethyl]amino}propyl)isonicotinamidewas afforded as an oil.

¹H NMR (300 MHz, CDCl₃) δ 8.55 (1H, s); 7.45 (1H, s); 6.47 (1H, t); 3.53(1H, dd); 3.21–3.16 (3H, m); 2.88 (2H, t); 2.81–2.69 (2H, m); 2.56–2.48(1H, m); 2.05–1.96 (3H, m); 1.96–1.88 (2H, m); 1.76–1.63 (6H, m);1.57–1.55 (6H, m); 1.03 (3H, d). MS: APCI(+ve) 420/422 (M+1)

The compound from above (0.060 g) was dissolved in dry hydrogen chloridein 1,4-dioxane (4N, 2 ml) and was concentrated. The residue wasrecrystallised from methanol:ethyl acetate to afford the titled compound(0.045 g) as a solid.

¹H NMR (300 MHz, DMSO-d₆) δ 8.62 (2H, br); 8.60 (1H, s); 8.53 (1H, t);7.35 (1H, s); 3.65 (1H, dd); 3.47 (1H, dd); 3.22 (1H, br); 2.94 (2H, d);2.85 (2H, t); 2.04 (2H, p); 1.98–1.96 (3H, m); 1.76–1.63 (6H, m);1.57–1.55 (6H, m); 1.18 (3H, d). MS: APCI(+ve) 420/422 (M+1) MP:205–208° C.

EXAMPLE 11N-(1-Adamantylmethyl)5-chloro-2-{3-[(2-hydroxyethyl)amino]propyl}-isonicotinamidehydrochloride

(i) tert-Butyl(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)prop-2-yn-1-ylcarbamate

The sub-titled compound was prepared from tert-butylprop-2-yn-1-ylcarbamate (0.8 g), 60% sodium hydride (0.227 g),(2-bromoethoxy)-tert-butyldimethylsilane (1 ml) and anhydrousN-methyl-2-pyrrolidinone (4 ml) by the method of Example 2(ii). Thecrude product was purified by chromatography on silica gel eluting withiso-hexane:ethyl acetate (25:1) to afford (0.8 g).

¹H NMR (300 MHz, CDCl₃) δ 4.13 (2H, broad); 3.75 (2H, broad t); 3.42(2H, t); 2.18 (1H, t); 1.47 (9H, s); 0.89 (9H, s); 0.04 (6H, s).

(ii) tert-Butyl3-(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)prop-2-ynyl(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)carbamate

The sub-titled compound was prepared from N-(1adamantylmethyl)-2-bromo-5-chloroisonicotinamide (Example 2(i)) (0.37g), tert-butyl(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)prop-2-yn-1-ylcarbamate(Example 11(i)) (0.54 g), copper (I) iodide (0.004 g),bis-triphenyphosphine palladium dichloride (0.014 g), triethylamine (6ml) and anhydrous acetonitrile (6 ml) by the method of Example 2(iii).The crude product was purified by chromatography on silica gel elutingwith, iso-hexane:ethyl acetate (8:1 to 4:1) to afford the sub-titledcompound (0.28 g) as a yellow gum.

¹H NMR (300 MHz, CDCl₃) δ 8.58 (1H, s); 7.67 (1H, s); 6.23 (1H, broad);4.40 (2H, m); 3.77 (2H, broad); 3.47 (2H, t); 3.18 (2H, d); 2.03 (3H,broad); 1.80–1.55 (12H, m); 1.48 (9H, s); 0.88 (9H, s); 0.05 (6H, s).

(iii)N-(1-Adamantylmethyl)-5-chloro-2-{3-[(2-hydroxyethyl)amino]propyl}-isonicotinamidehydrochloride

The titled compound was prepared from tert-butyl3-(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)prop-2-ynyl(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)carbamate(Example 11(ii)) (0.28 g) by the method of Example 6(ii). The crudehydrochloride salt was triturated with ethyl acetate to afford thetitled compound (0.176 g) as a beige powder.

¹H NMR (300 MHz, DMSO-d₆) δ 8.75 (2H, broad); 8.60 (1H, s); 8.53 (1H,t); 7.35 (1H, s); 3.65 (2H, t); 3.05–2.90 (6H, m); 2.84 (2H, t); 2.04(2H, quintet); 1.95 (3H, s); 1.64 (6H, q); 1.52 (6H, s). MS: APCI(+ve)406/408 (M+1). MP: 204–205° C. (dec.)

EXAMPLE 12N-(1-Adamantylmethyl)-5-chloro-2-{2-[(3-hydroxypropyl)amino]ethoxy}isonicotinamide,hydrochloride

(i) N-(1-Adamantylmethyl)-5-chloro-2-(2-hydroxyethoxy)isonicotinamide

Sodium hydride (60%, 0.080 g) was added to ethylene glycol (3 ml) andthe resulting suspension stirred under an atmosphere of nitrogen for 30minutes. To this mixture was added a solution ofN-(1-adamantylmethyl)-2-bromo-5-chloroisonicotinamide (Example 1(ii))(0.192 g) in anhydrous N-methyl-2-pyrrolidinone (1 ml). The stirring barwas removed and the resulting solution heated in a MARS microwave for 15minutes (300 Watts, 150° C.). The mixture was cooled and poured intowater (50 ml) and extracted into is ethyl acetate (3×10 ml). Thecombined organic extracts were washed with brine (2×10 ml), dried overanhydrous magnesium sulfate, filtered and concentrated. The residue waspurified by chromatography on silica gel eluting with ethylacetate:isohexane (1:1) to afford the sub-titled compound (0.092 g) as awhite solid.

¹H NMR (300 MHz, CDCl₃) δ 8.16 (1H, s); 7.09 (1H, s); 6.20 (1H, br);4.45 (2H, dd); 3.96 (2H, ddd); 3.17 (2H, d); 2.54 (1H, t); 2.05–1.96(3H, m); 1.76–1.73 (3H, m); 1.66–1.63 (3H, m); 1.57–1.55 (6H, m). MS:APCI(+ve) 364/366 (M+1) MP: 154–155° C.

(ii)N-(1-Adamantylmethyl)-5-chloro-2-{2-[(3-hydroxypropyl)amino]ethoxy}isonicotinamide,hydrochloride

To a stirred solution ofN-(1-adamantylmethyl)-5-chloro-2-(2-hydroxyethoxy)isonicotinamide(Example 12(i)) (0.10 g) in dry dichloromethane (5 ml) was addedDess-Martin periodinane (0.212 g) and the resulting suspension stirredat room temperature for 30 minutes. The reaction was poured into amixture of saturated sodium bicarbonate solution containing sodiumthiosulfate (10% w/v, 20 ml) and the mixture was extracted into ethylacetate (3×25 ml). The combined extracts were dried over anhydrousmagnesium sulfate, filtered and concentrated. The crude aldehyde wasdissolved in methanol (2 ml) and 3-aminopropan-1-ol (0.075 g) addedalong with acetic acid (0.1 ml). The mixture was stirred for 2 hours atambient temperature and then sodium triacetoxy borohydride (0.159 g)added and the reaction stirred for 20 hours, concentrated and theresidue was partitioned between 2M aqueous hydrochloric acid solutionand ethyl acetate (2×10 ml). The layers were separated and the organicphase re-extracted with 2N hydrochloric acid (2×10 ml). The combinedaqueous extracts were basified with 5M aqueous ammonium hydroxidesolution, extracted into ethyl acetate (2×25 ml) and the combinedextracts were dried over anhydrous magnesium sulfate, filtered andconcentrated to afford the compound,N-(1-adamantylmethyl)-5-chloro-2-{2-[(3-hydroxypropyl)amino]ethoxy}isonicotinamide(0.05 g), as a foam.

¹H NMR (400 MHz, CDCl₃) δ 8.15 (1H, s); 7.01 (1H, s); 6.31 (1H, br);4.41 (2H, t); 3.80 (2H, d); 3.16 (2H, d); 3.00 (2H, t); 2.94 (3H, t);2.05–1.96 (3H, m); 1.76–1.73 (5H, m); 1.66–1.63 (3H, m); 1.57–1.55 (6H,m). MS: APCI(+ve) 421/423 (M+1)

The compound from above (0.050 g) was dissolved in dry hydrogen chloridein 1,4-dioxane (4N, 2 ml) and was concentrated. The residue wastriturated with dry ether and filtered to affordN-(1-adamantylmethyl)-5-chloro-2-{2-[(3-hydroxypropyl)amino]ethoxy}isonicotinamidehydrochloride (0.024 g) as a white solid.

¹H NMR (300 MHz, DMSO-d₆) δ 8.85 (2H, broad); 8.57 (1H, s); 8.54 (1H,t); 8.34 (1H, s); 6.86 (1H, s); 4.53 (2H, t); 3.54 (2H, t); 3.38–3.32(2H, m); 3.06–3.02 (2H, m); 2.94 (2H, d); 1.94 (3H, s); 1.88–1.82 (2H,m); 1.76–1.73 (3H, m); 1.66–1.63 (3H, m); 1.57–1.55 (6H, m). MS:APCI(+ve) 421/423 (M+1)

EXAMPLE 13N-(1-Adamantylmethyl)-5-chloro-2-({2-[(2-hydroxyethyl)amino]ethyl}-amino)isonicotinamidedihydrochloride

(i) tert-Butyl2-[(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)(2-hydroxyethyl)amino]ethylcarbamate

N-(2-Hydroxyethyl)-ethylenediamine (0.208 g) was added to a mixture ofN-(1-adamantylmethyl)-2-bromo-5-chloroisonicotinamide (0.192 g, Example1(ii)) and potassium carbonate (0.14 g) in anhydrousN-methyl-2-pyrrolidinone (3 ml). The resulting solution heated in a MARSmicrowave for 10 minutes (300 Watts, 150° C.). The mixture was cooledand poured into water (50 ml) and extracted into ethyl acetate (3×10ml). The combined organic extracts were washed with brine (2×10 ml),dried over anhydrous magnesium sulfate, filtered and concentrated. Theresidue was dissolved into ethyl acetate 30 ml anddi-tert-butylcarbonate (0.218 g) added. The resulting mixture was leftto stand at room temperature for 2 hours and was then concentrated underreduced pressure. The residue was purified by chromatography on silicagel eluting with ethyl acetate to afford tert-butyl2-[(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)(2-hydroxyethyl)amino]ethylcarbamate(0.013 g).

¹H NMR (300 MHz, CDCl₃) δ 8.08 (1H, s); 6.96 (1H, s); 6.43 (1H, br);4.95 (1H, br); 3.83 (2H, t); 3.70–3.62 (4H, m); 3.67 (2H, q); 3.17 (2H,d); 2.05–1.96 (3H, m); 1.76–1.73 (3H, m); 1.66–1.63 (3H, m); 1.57–1.55(6H, m); 1.37 (9H, s). MS: APCI(+ve) 507, 509 (M+1)

(ii)N-(1-Adamantylmethyl)-5-chloro-2-({2-[(2-hydroxyethyl)amino]ethyl}-amino)isonicotinamidedihydrochloride

tert-Butyl2-[(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)(2-hydroxyethyl)amino]ethylcarbamate(Example 13(i)) (0.013 g) was dissolved in anhydrous hydrogen chloridein 1,4-dioxane (4M, 2 ml) and the resulting mixture was allowed to standat room temperature for 30 minutes. The mixture was concentrated underreduced pressure to afford the titled product (0.020 g).

¹H NMR (300 MHz, DMSO-d₆) δ 8.39 (1H, t); 8.11 (1H, s); 7.85 (2H, br);6.69 (1H, s); 3.74 (2H, t); 3.07–3.96 (4H, br); 2.92 (2H, d); 1.94 (3H,s); 1.76–1.73 (3H, m); 1.66–1.63 (3H, m); 1.57–1.55 (6H, m). MS:APCI(+ve) 407, 409 (M+1)

EXAMPLE 14N-(1-Adamantylmethyl)-5-chloro-2-[3-(isopropylamino)propyl]isonicotinamidedihydrochloride

(i)N-(1-Adamantylmethyl)-2-(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)-5-chloroisonicotinamide

A solution of 9-borabicyclo[3.3.1]nonane at 0.5 M in tetrthydrofuran(2.78 mL, 1.39 mmol) was added to neat(allyloxy)(tert-butyl)dimethylsilane (0.15 mL, 0.69 mmole). The mixturewas heated to 60° C. for 2 hours under nitrogen. The reaction wassubsequently cooled to room temperature and a solution of potassiumphosphate (0.37 g) in water (1 mL) was added slowly. A solution ofN-(1-adamantylmethyl)-2,5-dichloroisonicotinamide (0.20 g, 0.59 mmol;prepared as described in WO 01/94338) in dimethylformamide (3 mL) wasadded followed by tetrakis(triphenyphosphine)palladium (0) (7 mg). Thesolution was heated to 70° C. for 2 hours; allowed to cool to roomtemperature then partitioned between ethyl acetate (20 mL) and brine (10mL). The aqueous phase was further extracted with ethyl acetate (2×20mL) and the combined organics were washed with brine (20 mL); dried overmagnesium sulphate; filtered and evaporated under vacuum to give thecrude product (0.70 g) as a yellow oil, which was used, as such, withoutany further purification.

(ii) N-(1-Adamantylmethyl)-5chloro-2-(3-hydroxypropyl)isonicotinamide

The residue from above was dissolved in tetrahydrofuran (10 mL) andcooled to 0° C. To this a solution of tetra-n-butyl ammonium fluoride(0.75 mL of a 1M solution) was added and the mixture warmed to roomtemperature for 2 hours. After this time the solution was cooled to 0°C. and treated with 0.6 mL of tetra-n-butyl ammonium fluoride andstirring continued for an additional hour at room temperature. Thereaction mixture was subsequently diluted with diethyl ether (30 mL);washed with water (2×10 mL); brine (20 mL); dried over magnesiumsulphate; filtered and evaporated under vacuum. The residue was purifiedby chromatography on silica gel eluting with dichloromethane:ethylacetate:methanol (15:4:1) to afford the sub-titled compound (0.21 g) asa clear oil.

¹H NMR (400 MHz, CDCl₃) δ 8.55 (1H, s); 7.51 (1H, s); 6.32 (1H, bs);3.69 (2H, t); 3.19 (2H, d); 2.96 (2H, t); 1.96–2.05 (5H, m); 1.70 (6H,q); 1.58 (6H, s) MS: APCI(+ve) 363, 365 (M+1).

(iii) N-(1-Adamantylmethyl)-5-chloro-2-(3-oxopropyl)isonicotinamide

To a stirred solution ofN-(1-adamantylmethyl)-5-chloro-2-(3-hydroxypropyl)isonicotinamide (0.12g, 0.33 mmol) (Example 14(ii)) in dry dichloromethane (10 mL)Dess-Martin periodinane (0.14 g, 0.33 mmol) was added. The resultingmixture was stirred at room temperature for 4 hours. The reaction wastreated with diethyl ether (20 mL) and a saturated sodium bicarbonatesolution containing sodium thiosulfate (0.37 g, in 4 mL). The mixturewas stirred for 10 minutes and the organics separated; washed with brine(10 mL); dried over anhydrous magnesium sulfate; filtered; treated withacetic acid (0.30 mL) and concentrated. MS: APCI(+ve) 361, 363 (M+1).

(iv)N-(1-Adamantylmethyl)-5-chloro-2-[3-(isopropylamino)propyl]isonicotinamidedihydrochloride

The crude aldehyde from above was dissolved in methanol (2 mL) andtreated with isopropylamine (0.084 mL, 0.99 mmol) along with acetic acid(0.10 mL). The mixture was stirred for 10 minutes at ambient temperatureand then sodium triacetoxy borohydride (0.14 g, 0.66 mmol) was added.The reaction was stirred for 20 hours, concentrated and the residuedissolved in ethyl acetate (20 mL). The organics were washed with asaturated solution of sodium bicarbonate (10 mL); brine (10 mL); driedover anhydrous magnesium sulfate; filtered and concentrated to afford anoil (0.118 g). The crude compound was dissolved in dichloromethane (5mL); treated with dry hydrogen chloride in 1,4-dioxane (4N, 0.4 mL) andwas concentrated after 10 minutes. The residue was filtered fromdichloromethane (20 mL) to afford the titled compound (0.098 g) as awhite solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.61–8.51 (3H, m); 3.32–3.26 (1H, m);2.95–2.84 (6H, m); 2.05–2.00 (2H, m); 1.98 (3H, s); 1.68 (6H, q); 1.59(6H, s); 1.22 (6H, d). MS: APCI(+ve) 404, 406 (M+1).

EXAMPLE 15N-(1-Adamantylmethyl)-5-chloro-2-(3-{[(2S)-2-hydroxypropyl]amino}propyl)isonicotinamide,dihydrochloride

By the method outlined for Example 14(iv) and using(2S)-1-aminopropan-2-ol, the compound,N-(1-adamantylmethyl)-5-chloro-2-(3-{[(2S)-2-hydroxypropyl]amino}propyl)isonicotinamide,was afforded as an oil. Purification was by preparative reverse phaseHPLC. The isolated material (0.081 g) was dissolved in a solution ofhydrogen chloride in 1,4-dioxane (1 mL of a 4M solution) andconcentrated to afford the titled compound as a colorless powder (0.091g).

¹H NMR (400 MHz, DMSO-d₆) δ 8.91 (1H, bs); 8.71(1H, bs); 8.60 (1H, s);8.56 (1H, t); 3.99–3.94 (1H, m); 2.95–2.94 (5H, m); 2.85 (2H, t);2.76–2.70 (1H, m); 2.10–2.02 (2H, m); 1.95 (3H, s); 1.64 (6H, q); 1.52(6H, s); 1.10 (3H, d). MS: APCI(+ve) 420, 422 (M+1).

EXAMPLE 16N-(1-Adamantylmethyl)-5-chloro-2-(3-{[(2R)-2,3-dihydroxypropyl]amino}propyl)isonicotinamide,dihydrochloride

By the method outlined for Example 14(iv) and using(2R)-3-aminopropane-1,2-diol, the compound,N-(1-adamantylmethyl)-5-chloro-2-(3-{[(2R)-2,3-dihydroxypropyl]amino}propyl)isonicotinamide,was afforded as an oil. The residue was purified by chromatography onsilica gel eluting with dichloromethane:methanol:ammonia (10:1:1). Theisolated material was dissolved in dichloromethane, treated with asolution of hydrogen chloride in 1,4-dioxane (1 mL of a 4M solution) andconcentrated to afford the titled compound as a colorless powder (0.098g).

¹H NMR (400 MHz, CD₃OD) δ 8.65–8.62 (2H, m); 7.44 (1H, s); 3.90–3.87(1H, m); 3.55 (2H, dq); 3.20–2.97 (8H, m); 2.18–2.11 (2H, m); 1.99 (3H,s); 1.73 (6H, q); 1.62 (6H, s). MS: APCI(+ve) 436, 438 (M+1). MP:217–219° C.

EXAMPLE 17N-(1-Adamantylmethyl)-5-chloro-2-(3-{[(2S)-2,3-dihydroxypropyl]amino}propyl)isonicotinamide,dihydrochloride

By the method outlined for Example 14(iv) and using(2S)-3-aminopropane-1,2-diol, the compound,N-(1-adamantylmethyl)-5-chloro-2-(3-{[(2S)-2,3-dihydroxypropyl]amino}propyl)isonicotinamide,was afforded as an oil. The residue was purified by chromatography onsilica gel eluting with dichloromethane:methanol:ammonia (10:1:1). Theisolated material was dissolved in dichloromethane, treated with asolution of hydrogen chloride in 1,4-dioxane (1 mL of a 4M solution) andconcentrated to afford the titled compound as a colorless powder (0.057g).

¹H NMR (400 MHz, CD₃OD) δ 8.64 (2H, s); 7.45 (1H, s); 3.92–3.89 (1H, m);3.55 (2H, dq); 3.20–2.97 (8H, m); 2.18–2.11 (2H, m); 1.99 (3H, s); 1.73(6H, q); 1.62 (6H, s). MS: APCI(+ve) 436, 438 (M+1).

EXAMPLE 18N-(1-Adamantylmethyl)-5-chloro-2-{3-[(4-methylcyclohexyl)amino]propyl}isonicotinamidedihydrochloride

By the method outlined for Example 14(iv) and using 4-aminocyclohexanol,the titled compound,N-(1-adamantylmethyl)-5-chloro-2-{3-[(4-methylcyclohexyl)amino]propyl}isonicotinamide,was afforded as an oil. Purification was by preparative reverse phaseHPLC. The isolated material (0.022 g) was dissolved in dichloromethane,treated with a solution of hydrogen chloride in 1,4-dioxane (1 mL of a4M solution) and concentrated to afford the titled compound as acolorless powder (0.025 g).

¹H NMR (300 MHz, CD₃OD) δ 8.63 (1H, s); 7.39 (1H, s); 3.61–3.58 (1H, m);3.10–3.01 (5H, m); 2.96 (2H, t); 2.19–2.00 (5H, m); 1.70 (6H, q); 1.64(6H, s); 1.47–1.30 (8H, m). MS: APCI(+ve) 460, 462 (M+1). MP: 242–244°C.

EXAMPLE 19N-(1-Adamantylmethyl)-5-chloro-2-{3-[(2-hydroxy-2-methylpropyl)amino]propyl}isonicotinamidedihydrochloride

By the method outlined for Example 14(iv) and using1-amino-2-methylpropan-2-ol, the titled compound,N-(1-adamantylmethyl)-5-chloro-2-{3-[(2-hydroxy-2-methylpropyl)amino]propyl}isonicotinamide,was afforded as an oil. Purification was by preparative reverse phaseHPLC. The isolated material (0.015 g) was dissolved in dichloromethane,treated with a solution of hydrogen chloride in 1,4-dioxane (1 mL of a4M solution) and concentrated to afford the titled compound as acolorless powder (0.019 g).

¹H NMR (300 MHz, CD₃OD) δ 8.65 (1H, s); 7.44 (1H, s); 3.16–3.09 (4H, m);3.01 (4H, t); 2.21–2.16 (2H, m); 2.00 (3H, s); 1.75 (6H, q); 1.64 (6H,d); 1.33 (6H, s). MS: APCI(+ve) 434, 436 (M+1). MP: 236–238° C.

EXAMPLE 20N-(1-Adamantylmethyl)-5-chloro-2-(3-{[(1R)-1-(hydroxymethyl)-2-methylpropyl]amino}propyl)isonicotinamide,dihydrochloride

By the method outlined for Example 14(iv) and using(2R)-2-amino-3-methylbutan-1-ol, the compound,N-(1-adamantylmethyl)-5-chloro-2-(3-{[(1R)-1-(hydroxymethyl)-2-methylpropyl]amino}propyl)isonicotinamide,was afforded as an oil. Purification was by preparative reverse phaseHPLC. The isolated material (0.065 g) was dissolved in dichloromethane,treated with a solution of hydrogen chloride in 1,4-dioxane (1 mL of a4M solution) and concentrated to afford the titled compound as acolorless powder (0.071 g).

¹H NMR (400 MHz, DMSO-d₆) δ 8.60 (1H, s); 8.54 (1H, bt); 8.36 (1H, bs);7.36 (1H, s); 3.72–3.68 (1H, m); 3.63–3.57 (2H, m); 3.16–3.04 (2H, bm);2.94 (2H, d); 2.87 (2H, t); 2.11–2.02 (4H, m); 1.95 (3H, s); 1.64 (6H,q); 1.52 (6H, s); 0.98 (3H, d); 0.94 (3H, d). MS: APCI(+ve) 448, 450(M+1).

EXAMPLE 21N-(1-Adamantylmethyl)-5-chloro-2-(3-{[2-(methylamino)ethyl]amino}propyl)isonicotinamidedihydrochloride

By the method outlined for Example 14(iv) and using tert-butyl2-aminoethyl(methyl)carbamate, tert-butyl2-{[3-(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)propyl]amino}ethyl(methyl)carbamatewas afforded as an oil. The latter (0.118 g) was dissolved indichloromethane and treated with dry hydrogen chloride in 1,4-dioxane(4N, 1 mL) and was concentrated after 2 hours to give the deprotectedmaterial. The residue was recrystallised from dichloromethane (3 ml) toafford the titled compound (0.035 g) as a white solid.

¹H NMR (300 MHz, CD₃OD) δ 8.71 (1H, s); 7.54 (1H, s); 3.43 (4H, s);3.22–3.17 (4H, m); 3.09–3.02 (4H, m); 2.81 (3H, s); 2.24–2.19 (2H, m);2.01 (3H, s); 1.75 (6H, q); 1.64 (6H, s); MS: APCI(+ve) 419, 421 (M+1).MP: 216–219° C.

EXAMPLE 22N-(1-Adamantylmethyl)-5-chloro-2-(3-{[3-(methylamino)propyl]amino}propyl)isonicotinamidebis(trifluoroacetate)

By the method outlined for Example 14(iv) and using tert-butyl3-aminopropyl(methyl)carbamate, tert-butyl3-{[3-(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)propyl]amino}propyl(methyl)carbamatewas afforded as an oil. The latter (0.121 g) was dissolved indichloromethane and treated with dry hydrogen chloride in 1,4-dioxane(4N, 1 mL) and was concentrated after 2 hours to give the deprotectedmaterial. The residue was purified by preparative reverse phase HPLC toafford the titled compound (0.028 g) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ 8.57 (1H, s); 7.33 (1H, s); 3.13–3.06 (8H, m);2.93 (2H, t); 2.72 (3H, s); 2.16–2.05 (4H, m); 1.98 (3H, s); 1.75 (6H,q); 1.62 (6H, s). MS: APCI(+ve) 433, 435 (M+1). MP: 210–212° C.

EXAMPLE 23N-(1-Adamantylmethyl)-5-chloro-2-[3-({2-[(2-hydroxyethyl)amino]ethyl}amino)propyl]isonicotinamidedihydrochloride

By the method outlined for Example 14(iv) and using tert-butyl2-aminoethyl(2-hydroxyethyl)carbamate, tert-butyl2-{[3-(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)propyl]amino}ethyl(2-hydroxyethyl)carbamatewas afforded as an oil. The latter (0.062 g) was dissolved indichloromethane and treated with dry hydrogen chloride in 1,4-dioxane(4N, 1 mL) and was concentrated after 2 hours to give the deprotectedmaterial. The residue was recrystallised from dichloromethane (3 mL) toafford the titled compound (0.006 g) as a white solid.

¹H NMR (300 MHz, CD₃OD) δ 8.61 (1H, s); 7.39 (1H, s); 3.86 (2H, t); 3.47(4H, t); 3.27–3.16 (4H, m); 3.10–3.08 (2H, m); 2.99 (2H, t); 2.22–2.17(2H, m); 2.01 (3H, s); 1.75 (6H, q); 1.64 (6H, d). MS: APCI(+ve) 449,451 (M+1). MP: 231–233° C.

EXAMPLE 24N-(1-Adamantylmethyl)-5-chloro-2-(3-{[2-(diethylamino)ethyl]amino}propyl)isonicotinamidedihydrochloride

By the method outlined for Example 14(iv) and usingN,N-diethylethane-1,2-diamine, the titled compound,N-(1-adamantylmethyl)5-chloro-2-(3-{[2-(diethylamino)ethyl]amino}propyl)isonicotinamide,was afforded as an oil. Purification was by preparative reverse phaseHPLC. The isolated material (0.057 g) was dissolved in dichloromethane,treated with a solution of hydrogen chloride in 1,4-dioxane (1 mL of a4M solution) and concentrated to afford the titled compound as acolorless powder (0.062 g).

¹H NMR (400 MHz, CD₃OD) δ 8.62 (1H, s); 7.43 (1H, s); 3.51 (4H, s);3.35–3.31 (2H, m); 3.18 (2H, t); 3.08 (2H, s); 2.99 (2H, t); 2.21–2.17(2H, m); 1.99 (3H, s); 1.74 (6H, q); 1.63 (6H, s). MS: APCI(+ve) 461,463 (M+1).

EXAMPLE 25N-(1-Adamantylmethyl)-5-chloro-2-(3-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}propyl)isonicotinamidedihydrochloride

By the method outlined for Example 14(iv) and using2-aminopropane-1,3-diol, the titled compound,N-(1-adamantylmethyl)-5-chloro-2-(3-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}propyl)isonicotinamide,was afforded as an oil. Purification was by preparative reverse phaseHPLC. The isolated material (0.072 g) was dissolved in dichloromethane,treated with a solution of hydrogen chloride in 1,4-dioxane (1 mL of a4M solution) and concentrated to afford the titled compound as acolorless powder (0.080 g).

¹H NMR (400 MHz, CD₃OD) δ 8.61 (1H, s); 7.40 (1H, s); 3.80 (2H, dd);3.73 (2H, dd); 3.19 (2H, t), 3.07 (2H, s); 2.99 (2H, t); 2.19–2.11 (2H,m); 1.98 (3H, s); 1.73 (6H, q); 1.61 (6H, s). MS: APCI(+ve) 436, 438(M+1). MP: 201–203° C.

EXAMPLE 26N-(1-Adamantylmethyl)-5chloro-2-{3-[(2-hydroxyethyl)(methyl)amino]propyl}isonicotinamidedihydrochloride

By the method outlined for Example 14(iv) and using2-(methylamino)ethanol, the titled compound,N-(1-adamantylmethyl)-5-chloro-2-{3-[(2-hydroxyethyl)(methyl)amino]propyl}isonicotinamide,was afforded as an oil. Purification was by preparative reverse phaseHPLC. The isolated material (0.061 g) was dissolved in dichloromethane,treated with a solution of hydrogen chloride in 1,4-dioxane (1 mL of a4M solution) and concentrated to afford the titled compound as a whitepowder (0.069 g).

¹H NMR (400 MHz, CD₃OD) δ 8.64 (2H, bs); 7.46 (1H, s); 3.87–3.84 (2H,m); 3.39–3.16 (4H, m); 3.07 (2H, s); 2.99 (2H, t); 2.91 (3H; s);2.24–2.16 (2H, m); 1.98 (3H, s); 1.73 (6H, q); 1.61 (6H, s). MS:APCI(+ve) 420, 422 (M+1). MP: 206–208° C.

EXAMPLE 27 N-(1-Adamantylmethyl)-5-chloro-2-{3-[(3-hydroxy-2,2-dimethylpropyl)amino]propyl}isonicotinamidedihydrochloride

By the method outlined for Example 14(iv) and using3-amino-2,2-dimethylpropan-1-ol, the titled compound,N-(1-adamantylmethyl)-5-chloro-2-{3-[(3-hydroxy-2,2-dimethylpropyl)amino]propyl}isonicotinamide,was afforded as an oil. The compound from above (0.122 g) was dissolvedin dichloromethane and treated with dry hydrogen chloride in 1,4-dioxane(4N, 0.4 mL) and was concentrated after 10 minutes. The residue wasfiltered from dichloromethane (20 mL) to afford the titled compound(0.091 g) as a solid.

¹H NMR (300 MHz, CD₃OD) δ 8.66 (1H, s), 7.44 (1H, s); 3.49 (2H, s);3.13–3.08 (4H, m); 3.01–2.96 (4H, m); 2.23–2.12 (2H, m); 2.00 (3H, s);1.75 (6H, q); 1.64 (6H, d); 1.05 (6H, s). MS: APCI(+ve) 448, 450 (M+1).

EXAMPLE 28N-(1-Adamantylmethyl)-5-chloro-2-(3-{[(2R)-2-hydroxypropyl]amino}propyl)isonicotinamide,dihydrochloride

By the method outlined for Example 14(iv) and using(2R)-1-aminopropan-2-ol, the compound,N-(1-adamantylmethyl)-5-chloro-2-(3-{[(2R)-2-hydroxypropyl]amino}propyl)isonicotinamide,was afforded as an oil. The compound from above (0.062 g) was dissolvedin dichloromethane and treated with dry hydrogen chloride in 1,4-dioxane(4N, 0.4 mL) and was concentrated after 10 minutes. The residue wasfiltered from dichloromethane (10 mL) to afford the titled compound(0.033 g) as a solid.

¹H NMR (400 MHz, CD₃OD) δ 8.57 (2H, bs); 7.35 (1H, s); 4.04–3.96 (1H,m); 3.10–3.06 (4H, m); 2.95 (2H, t); 2.85 (2H, t); 2.16–2.10 (2H, m);1.98 (3H, s); 1.73 (6H, q); 1.62 (6H, s); 1.21 (3H, d). MS: APCI(+ve)420, 422 (M+1). MP: 224–226° C.

EXAMPLE 29N-(1-Adamantylmethyl)-5chloro-2-({[3-(methylamino)propyl]amino}methyl)isonicotinamidedihydrochloride

(i) N-(1-Adamantylmethyl)-5chloro-2-vinylisonicotinamide

N-(1-Adamantylmethyl)-2,5-dichloroisonicotinamide (2.32 g) andtributyl(vinyl)stannane (2.61 g) were stirred together in dryN,N-dimethylformamide (50 mL) at room temperature under nitrogen. Thelatter was treated with a few crystals of2,6-ditert-butyl-4-methylphenol anddichloro[bis(triphenylphosphine)]palladium(II) (0.24 g). The reactionmixture was warmed to 80° C. for 4 hours and subsequently cooled to roomtemperature. The mixture was poured into ethyl acetate (50 mL) andwashed with water (2×25 mL) then brine (30 mL). The organics were driedover anhydrous magnesium sulfate, filtered and concentrated. The residuewas purified by chromatography on silica gel eluting with ethylacetate:dichloromethane (1:20) to afford the sub-titled compound (2.21g).

¹H NMR (300 MHz, CDCl₃) δ 8.58 (1H, s); 7.62 (1H, s); 6.79 (1H, dd);6.36 (1H, bs); 6.25 (1H, dd); 5.56 (1H, dd); 3.19 (2H, d); 1.98 (3H, s);1.70 (6H, q); 1.59 (6H, s). MS: APCI(+ve) 331, 333 (M+1).

(ii) N-(1-Adamantylmethyl)-5-chloro-2-formylisonicotinamide

N-(1-Adamantylmethyl)-5-chloro-2-vinylisonicotinamide (Example 29(i))(1.70 g) was dissolved in dichloromethane (50 mL), treated with aceticacid (1 mL) and cooled to −78° C. under nitrogen. Ozone was bubbledthrough the resulting solution for 2 hours while maintaining thetemperature. Nitrogen was subsequently bubbled through the solution for10 minutes and dimethylsulfide (2 mL) was added. The solution was warmedto room temperature washed with sodium bicarbonate (2×10 mL) and brine(30 mL); the organics were dried over anhydrous magnesium sulfate,filtered and concentrated. The residue was purified by chromatography onsilica gel eluting with ethyl acetate:dichloromethane (1:20) to affordthe sub-titled compound (1.13 g).

¹H NMR (300 MHz, CDCl₃) δ 10.06 (1H, s); 8.81 (1H, s); 8.15 (1H, s);6.20 (1H, bs); 3.17 (2H, d); 2.02 (3H, s); 1.70 (6H, q); 1.58 (6H, s).MS: APCI(+ve) 333, 335 (M+1).

(iii)N-(1-Adamantylmethyl)-5-chloro-2-({[3-(methylamino)propyl]amino}methyl)isonicotinamidedihydrochloride

N-(1-Adamantylmethyl)-5-chloro-2-formylisonicotinamide (Example 29(ii))(0.2 g) was dissolved in methanol (10 mL) and tert-butyl3-aminopropyl(methyl)carbamate, (0.39 g) added along with acetic acid(0.2 mL). The mixture was stirred for 15 minutes at ambient temperatureand then sodium triacetoxyborohydride (0.25 g) was added and thereaction stirred for 20 hours, concentrated and the residue partitionedbetween 2M aqueous hydrochloric acid solution (10 mL) and ethyl acetate(10 mL). The layers were separated and the organic phase re-extractedwith 2N hydrochloric acid (2×10 mL). The combined aqueous extracts werebasified with 5M aqueous ammonium hydroxide solution, extracted intoethyl acetate (2×25 mL) and the combined extracts were dried overanhydrous magnesium sulfate, filtered and concentrated. The residue wasdissolved in dichloromethane and treated with dry hydrogen chloride in1,4-dioxane (4N, 1 mL) and was concentrated after 2 hours to give thedeprotected material. The residue was recrystallised fromdichloromethane (10 mL) to afford the titled compound (0.110 g).

¹H NMR (300 MHz, CD₃OD) δ 8.75 (1H, s); 8.67 (1H, bt); 7.56 (1H, s);4.48 (2H, s); 3.27 (2H, t); 3.18–3.09 (4H, m); 2.75 (3H, s); 2.25–2.15(2H, m); 2.01 (3H, s); 1.76 (6H, q); 1.65 (6H, s). MS: APCI(+ve) 405,407 (M+1). MP: 285–287° C.

EXAMPLE 30N-(1-Adamantylmethyl)-5-chloro-2-[({2-[(2-hydroxyethyl)amino]ethyl}amino)methyl]isonicotinamidedihydrochloride

By the method outlined for Example 29 (iii) and using tert-butyl2-aminoethyl(2-hydroxyethyl)carbamate, tert-butyl2-{[(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)methyl]amino}ethyl(2-hydroxyethyl)carbamatewas afforded as an oil. The latter was dissolved in dichloromethane andtreated with dry hydrogen chloride in 1,4-dioxane (4N, 1 mL) and wasconcentrated after 2 hours to give the deprotected material. The residuewas recrystallised from dichloromethane (5 mL) to afford the titledcompound (0.118 g) as a white solid.

¹H NMR (400 MHz, CD₃OD) δ 8.76 (1H, s); 8.64 (1H, t); 7.55 (1H, s); 4.51(2H, s); 3.85–3.83 (2H, m); 3.57–3.32 (4H, m); 3.23–3.21 (2H, m); 3.08(2H, d); 1.99 (3H, s); 1.74 (6H, q); 1.62 (6H, s). MS: APCI(+ve) 421,423 (M+1). MP: 289–292° C.

EXAMPLE 31N-(1-Adamantylmethyl)-5-chloro-2-({[2-(methylamino)ethyl]amino}methyl)isonicotinamidedihydrochloride

By the method outlined for Example 29 (iii) and using tert-butyl2-aminoethyl(methyl)carbamate, tert-butyl2-{[(4-{[(1-adamantylmethyl)amino]carbonyl}-5-chloropyridin-2-yl)methyl]amino}ethyl(methyl)carbamatewas afforded as an oil. The latter was dissolved in dichloromethane andtreated with dry hydrogen chloride in 1,4-dioxane (4N, 1 mL) and wasconcentrated after 3 hours to give the deprotected material.Purification was by preparative reverse phase HPLC. The compound (0.058g) was subsequently dissolved in dichloromethane and treated with dryhydrogen chloride in 1,4-dioxane (4N, 0.4 mL) and was concentrated after10 minutes to give the desired compound as a white solid (0.062 g).

¹H NMR (400 MHz, CD₃OD) δ 8.73 (1H, s); 8.66 (1H, t); 7.55 (1H, s); 4.54(2H, s); 3.58–3.55 (2H, m); 3.50–3.47 (2H, m); 3.08 (2H, d); 2.81 (3H,s); 1.99 (3H, s); 1.74 (6H, q); 1.63 (6H, s). MS: APCI(+ve) 391, 393(M+1). MP: 259–262° C.

EXAMPLE 32N-(1-Adamantylmethyl)-5-chloro-2-{3-[(2-hydroxyethyl)amino]ethyl}isonicotinamidedihydrochloride

N-(1-Adamantylmethyl)-5-chloro-2-vinylisonicotinamide (0.37 mmolar, 125mg) (Example 29(i) was dissolved in a mixture of methanol (1 mL),isopropanol (1 mL) and acetic acid (1 mL). The resulting solution wastreated with 2-aminoethanol (1 mL) and heated to 100° C. for 18 h Thesolution was allowed to cool to room temperature, poured into saturatedsodium bicarbonate solution (20 mL) and extracted with dichloromethane(2×20 mL). The combined organic extracts were dried over anhydrousmagnesium sulfate, filtered and concentrated. The residue was purifiedby chromatography on silica gel eluting withmethanol:dichloromethane:ammonia (10:30:0.1). The isolated material wasdissolved in a solution of hydrogen chloride in 1,4-dioxane (1 mL of a4M solution) and concentrated to afford the titled compound as acolorless powder (0.027 g).

¹H NMR (400 MHz, DMSO-d₆) δ 8.95 (2H, m); 8.62 (1H, s); 8.55 (1H, t);7.41 (1H, s); 3.68 (2H, t); 3.32 (2H, m); 3.20 (2H, m); 3.04 (2H, m);2.95 (2H, d); 1.95 (3H, m); 1.71–1.57 (6H, m); 1.53 (6H, m). MS:APCI(+ve) 392, 394 (M+1). MP: 242–244° C.

EXAMPLE 33N-(1-Adamantylmethyl)-5-chloro-2-{3-[(3-hydroxypropyl)amino]ethyl}isonicotinamidedihydrochloride

N-(1-Adamantylmethyl)-5-chloro-2-vinylisonicotinamide (0.37 mmolar, 125mg) (Example 29(i)) was dissolved in a mixture of methanol (1 mL),isopropanol (1 mL) and acetic acid (1 mL). The resulting solution wastreated with 3-aminopropanol (1 mL) and heated to 100° C. for 18 h. Thesolution was allowed to cool to room temperature, poured into saturatedsodium bicarbonate solution (20 mL) and extracted with dichloromethane(2×20 mL). The combined organic extracts were dried over anhydrousmagnesium sulfate, filtered and concentrated. The residue was purifiedby chromatography on silica gel eluting withmethanol:dichloromethane:ammonia (10:30:0.1). The isolated material wasdissolved in a solution of hydrogen chloride in 1,4-dioxane (1 mL of a4M solution) and concentrated to afford the titled compound as acolorless powder (0.025 g).

¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (2H, m); 8.62 (1H, s); 8.54 (1H, t);7.43 (1H, s); 3.50 (2H, t); 3.30 (2H, m); 3.17 (2H, m); 3.02 (2H, m);2.95 (2H, d); 1.95 (3H, m); 1.78 (2H, quintet); 1.71–1.57 (6H, m); 1.53(6H, m). MS: APCI(+ve) 406, 408 (M+1). MP: 240–242° C.

EXAMPLE 34N-(1-Adamantylmethyl)-5-chloro2-[3-(methylamino)propyl]isonicotinamidehydrochloride

A solution of tert-butyl allyl(methyl)carbamate (0.27 g) in9-boroabicyclo[3.3.1]nonane (6.24 ml of a 0.5M solution intetrahydrofuran) was heated at reflux under nitrogen for 4 hours. Thesolution was cooled to 0° C. and potassium phosphate (1.5 mI of a 3Msolution in water) was added. The mixture was stirred for 15 minutes anda solution of N-(1-adamantylmethyl)-2-bromo-5-chloroisonicotinamide(Example 1(ii)) (0.50 g) anddichloro[1,1′-bis(diphenylphosphino)ferrocenyl]palladium (II) (0.045 g)in anhydrous N,N-dimethylformamide (4 ml) was added. The mixture washeated at 60° C. under nitrogen for 3 hours, diluted with saturatedbrine (25 ml) and extracted into ethyl acetate (3×25 ml). The combinedextracts were dried over anhydrous sodium sulphate, filtered andconcentrated. The residue was purified by chromatography on silica geleluting with iso-hexane:ethyl acetate (6:1 to 1.5:1). The isolatedmaterial (0.50 g) was dissolved in a solution of hydrogen chloride in1,4-dioxane (10 ml of a 4M solution) and concentrated; the resultantsolid was recrystallised from 1,4-dioxane/methanol and the solidcollected by is filtration to afford the titled compound (0.19 g) as acolourless powder.

¹H NMR (400 MHz, DMSO-d₆) δ 8.84 (2H, broad); 8.60 (1H, s); 8.53 (1H,t); 7.35 (1H, s); 2.95–2.82 (6H, m); 2.02 (2H, q); 1.95 (3H, s); 1.64(6H, q); 1.52 (6H, s). MS: APCI(+ve) 378/376 (M+1) MP: 210–212° C.

EXAMPLE 35N-(1-Adamantylmethyl)-5-bromo-2-{[(2S)-2-hydroxy-3-(methylamino)propyl]oxy}isonicotinamide

(i) N-(1-Adamantylmethyl)-5-bromo-2-methoxyisonicotinamide

n-Butyllithium (2.51 ml of a 2.5M solution in hexanes) was added todiisopropylamine (0.88 ml) in dry tetrahydrofuran,(15 ml) at 65° C. Tothis solution was added a solution of 5-bromo-2-methoxypyridine (0.82ml) in dry tetrahydrofuran (10 ml) dropwise over 30 minutes at −65° C. Asolution of 1-adamantylmethylisocyanate (1 g) in dry tetrahydrofuran (10ml) was then added in small portions over 30 minutes at −65° C. Thereaction mixture was allowed to warm to 0° C., diluted with saturatedbrine (20 ml) and extracted into ethyl acetate (3×20 ml). The combinedextracts were dried over anhydrous sodium sulphate, filtered andconcentrated. The residue was purified by chromatography on silica geleluting with dichloromethane:acetone (19:1 to 2.5:1) to afford thesub-titled compound (1.1 g) as a colourless powder.

MS: APCI(+ve) 381/379 (M+1)

(ii) N-(1-Adamantylmethyl)-5-bromo-2-hydroxyisonicotinamide

Sodium iodide (0.48 g) was added to a solution of trimethylsilylchloride(0.41 ml) in acetonitrile (30 ml) and the mixture was stirred for 1hour. N-(1-Adamantylmethyl)-5-bromo-2-methoxyisonicotinamide (0.94 g)(Example 35(i)) was then added and the reaction mixture was heated at60° C. under nitrogen for 3 hours. The reaction mixture was diluted withwater (150 ml) and the resultant solid was collected by filtration anddried by means of ethanol/toluene azeotrope. The solid was trituratedwith diethyl ether and collected by filtration to afford the sub-titledcompound (0.70 g).

(iii)N-(1-Adamantylmethyl)-5-bromo-2-[(2S)-oxiran-2-ylmethoxy]isonicotinamide

A suspension of (S)-glycidyl nosylate (0.29 g), caesium carbonate (1.82g) and N-(1-adamantylmethyl)-5-bromo-2hydroxyisonicotinamide (0.41 g)(Example 35(ii)) in anhydrous N,N-dimethylformamide (6 ml) was heated at60° C. under nitrogen for 2 hours. The reaction mixture was allowed tocool to room temperature, diluted with water (50 ml) and extracted intoethyl acetate (3×20 ml). The combined extracts were dried over anhydroussodium sulphate, filtered and concentrated. The residue was purified bychromatography on silica gel eluting with dichloromethane:ethyl acetate(4:1 to 0:1) to afford the sub-titled compound (0.12 g).

MS: APCI(+ve) 423/421 (M+1)

(iv)N-(1-Adamantylmethyl)-5-bromo-2-{[(2S)-2-hydroxy-3-(methylamino)propyl]oxy}isonicotinamide

A mixture ofN-(1-adamantylmethyl)-5-bromo-2-[(2S)-oxiran-2-ylmethoxy]isonicotinamide(0.12 g) (Example 35(iii)), 40% aqueous methylamine (4 ml) and1,4-dioxane (4 ml) was stirred for 4 hours. The reaction mixture wasconcentrated and the residue was purified by chromatography on silicagel eluting with ethyl acetate:ethanol:0.880 ammonia solution (4:1:0.1to 1.5:1:0.1). The isolated material was dissolved in a solution ofhydrogen chloride in 1,4-dioxane (10 ml of a 4M solution) andconcentrated to afford the titled compound (0.039 g).

¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (1H, broad); 8.60 (1H, broad); 8.49(1H, t): 8.36 (1H,s); 6.83 (1H, s); 5.87 (1H,d); 4.3–4.1 (3H, m); 2.92(2H, d); 2.57 (3H, broad triplet); 1.94 (3H, s); 1.64 (6H, q); 1.52 (6H,s). MS: APCI(+ve) 454/452 (M+1)

EXAMPLE 36N-(1-Adamantylmethyl)-2-({3-[bis(3-hydroxypropyl)amino]propyl}amino)-3-chloroisonicotinamidedihydrochloride

(i) tert-Butyl3-[(4-{[(1-adamantylmethyl)amino]carbonyl}-3-chloropyridin-2-yl)amino]propylcarbamate

N-(1-Adamantylmethyl)-2,3-dichloroisonicotinamide (0.4 g) and tert-butyl3-aminopropylcarbamate (0.4 g) in DMSO (4 ml) were heated in a sealedtube at 160 C for 5 hrs. Ethyl acetate was added and the solution waswashed with NaHCO₃ solution, water, KHSO₄ solution and water. Thesolution was dried and the solvent was evaporated. The resulting oil wassubjected to flash chromatography, using ethyl acetate/hexane as eluant,to give the title compound as a colourless oil (0.41 g).

MS (ES+) 477, 479

(ii)N-(1-Adamantylmethyl)-2-[(3-aminopropyl)amino]-3-chloroisonicotinamidedihydrochloride

tert-Butyl3-[(4-{[(1-adamantylmethyl)amino]carbonyl}-3-chloropyridin-2-yl)amino]propylcarbamate(0.41 g) Example 36(i)) in methanol (15 ml) was treated with a solutionof HCl in 1,4-dioxane (4 ml) and the mixture was stirred at roomtemperature for 18 hrs. The solution was evaporated. Methanol was addedand the solution was evaporated to give the title compound as a paleyellow solid.

MS (ES+) 377, 379

(iii)N-(1-Adamantylmethyl)-2-({3-[bis(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)amino]propyl}amino)-3-chloroisonicotinamide

ToN-(1-adamantylmethyl)-2-[(3-aminopropyl)amino]-3-chloroisonicotinamide(0.32 g) (Example 36(ii)) and 3-{[tert-butyl(dimethyl)silyl]oxy}propanal(0.16 g) in dichloromethane (15 ml) was added sodiumtriacetoxyborohydride (0.18 g). The mixture was stirred for 18 hrs atroom temperature. NaHCO₃ solution was added and the product wasextracted into dichloromethane. The solution was dried and the solventwas evaporated. Flash chromatography, using NH₃/MeOH/CH₂Cl₂ as eluent,gave the title compound as a colourless oil.

(iv)N-(1-Adamantylmethyl)-2-({3-[bis(3-hydroxypropyl)amino]propyl}amino)-3-chloroisonicotinamidedihydrochloride

N-(1-adamantylmethyl)-2-({3-[bis(3-{[tert-butyl(dimethyl)silyl]oxy}propyl)amino]-propyl}amino)3-chloroisonicotinamide(Example 36(iii)) in methanol (5 ml) was treated with HCl in 1,4-dioxane(3 ml). The mixture was stirred at room temperature for 3 hrs. Thesolvent was evaporated. The product was purified by reverse phase HPLC,using NH₃/H₂O/CH₃CN as eluant. The resulting oil in methanol was treatedwith ethereal HCl and the solvent was evaporated to yield the titlecompound as a white solid (0.14 g).

¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (1H, t), 8.10 (1H, d), 6.86 (1H, d),3.65–3.74 (6H, m), 3.30–3.36 (6H, m), 3.075 (2H, d), 2.12–2.22 (2H, m),1.93–2.02 (7H, m), 1.77 (3H, d), 1.69 (3H, d), 1.62 (6H, s). MS (APCI+)493, 495 [M+H]⁺

Pharmacological Analysis

Certain compounds such as benzoylbenzoyl adenosine triphosphate (bbATP)are known to be agonists of the P2X₇ receptor, effecting the formationof pores in the plasma membrane (Drug Development Research (1996), 37(3)p. 126). Consequently, when the receptor is activated using bbATP in thepresence of ethidium bromide (a fluorescent DNA probe), an increase inthe fluorescence of intracellular DNA-bound ethidium bromide isobserved. The increase in fluorescence can be used as a measure of P2X₇receptor activation and therefore to quantify the effect of a compoundon the P2X₇ receptor.

In this manner, each of the title compounds of the Examples was testedfor antagonist activity at the P2X₇ receptor. Thus, the test wasperformed in 96-well flat bottomed microtitre plates, the wells beingfilled with 250 μl of test solution comprising 200 μl of a suspension ofTHP-1 cells (2.5×10₆ cells/ml) containing 10⁻⁴M ethidium bromide, 25 μlof a high potassium buffer solution containing 10⁻⁵M bbATP, and 25 μl ofthe high potassium buffer solution containing 3×10⁻⁵M test compound. Theplate was covered with a plastics sheet and incubated at 37° C. for onehour. The plate was then read in a Perkin-Elmer fluorescent platereader, excitation 520 nm, emission 595 nm, slit widths: Ex 15 nm, Em 20nm. For the purposes of comparison, bbATP (a P2X₇ receptor agonist) andpyridoxal 5-phosphate (a P2X₇ receptor antagonist) were used separatelyin the test as controls. From the readings obtained, a pIC₅₀ figure wascalculated for each test compound, this figure being the negativelogarithm of the concentration of test compound necessary to reduce thebbATP agonist activity by 50%. Each of the compounds of the Examplesdemonstrated antagonist activity, having a pIC₅₀ figure>4.50. Forexample, the compounds of Example 12 and Example 26 had pIC₅₀ values of7.1 and 7.8 respectively.

1. A compound of formula

wherein m represents 1, 2 or 3; each R¹ independently represents ahydrogen or halogen atom; A represents C(O)NH or NHC(O); Ar represents agroup

one of R² and R³ represents halogen, nitro, amino, hydroxyl, or a groupselected from (i) C₁–C₆ alkyl optionally substituted by at least onehalogen atom, (ii) C₃–C₈ cycloalkyl, (iii) C₁–C₆ alkoxy optionallysubstituted by at least one halogen atom, and (iv) C₃–C₈ cycloalkyloxy,and the other of R² and R³ represents a hydrogen or halogen atom; R⁴represents a group

X represents an oxygen or sulphur atom or a group >N—R⁸; n is 0 or 1; R⁵represents a C₁–C₅ alkyl group which may be optionally substituted by atleast one substituent selected from hydroxyl, halogen and C₁–C₆ alkoxy;R⁶ and R⁷ each independently represent a hydrogen atom, C₁–C₆ alkyl(optionally substituted by at least one substituent selected fromhydroxyl, halogen, C₁–C₆ alkoxy, and (di)-C₁–C₄ alkylamino (itselfoptionally substituted by at least one hydroxyl group)), or C₃–C₈cycloalkyl (optionally substituted by at least one substituent selectedfrom hydroxyl, halogen and C₁–C₆ alkoxy); and R⁸ represents a hydrogenatom or a C₁–C₅ alkyl group which may be optionally substituted by atleast one substituent selected from hydroxyl, halogen and C₁–C₆ alkoxy;with the provisos that: (a) when n is 0, then A is NHC(O), and (b) whenn is 1, X represents oxygen and A is C(O)NH, then R⁶ and R⁷ do not bothsimultaneously represent a hydrogen atom or do not both simultaneouslyrepresent an unsubstituted C₁–C₆ alkyl, or when one of R⁶ and R⁷represents a hydrogen atom, then the other of R⁶ and R⁷ does notrepresent an unsubstituted C₁–C₆ alkyl; and (c) when n is 1, X isoxygen, sulphur or NH and A is NHC(O), then R⁶ and R⁷ do not bothsimultaneously represent a hydrogen atom or do not both simultaneouslyrepresent an unsubstituted C₁–C₆ alkyl, or when one of R⁶ and R⁷represents a hydrogen atom, then the other of R⁶ and R⁷ does notrepresent an unsubstituted C₁–C₆ alkyl or —CH₂CH₂OH; or apharmaceutically acceptable salt or solvate thereof.
 2. A compound offormula (I) according to claim 1, wherein m represents 1, 2 or 3; eachR¹ independently represents a hydrogen or halogen atom; A representsC(O)NH or NHC(O); Ar represents a group

one of R² and R³ represents halogen, nitro, amino, hydroxyl, or a groupselected from (i) C₁–C₆ alkyl optionally substituted by at least onehalogen atom, (ii) C₃–C₈ cycloalkyl, (iii) C₁–C₆ alkoxy optionallysubstituted by at least one halogen atom, and (iv) C₃–C₈ cycloalkyloxy,and the other of R² and R³ represents a hydrogen or halogen atom; R⁴represents a group

X represents an oxygen or sulphur atom or a group >N—R⁸; n is 0 or 1; R⁵represents a C₁–C₅ alkyl group which may be optionally substituted by atleast one substituent selected from hydroxyl, halogen and C₁–C₆ alkoxy;and R⁶,R⁷ and R⁸ each independently represent a hydrogen atom or a C₁–C₅alkyl group which may be optionally substituted by at least onesubstituent selected from hydroxyl, halogen and C₁–C₆ alkoxy; with theprovisos that: (d) when n is 0, then A is NHC(O), and (e) when n is 1, Xrepresents oxygen and A is C(O)NH, then R⁶ and R⁷ do not bothsimultaneously represent a hydrogen atom or do not both simultaneouslyrepresent an unsubstituted C₁–C₅ alkyl, or when one of R⁶ and R⁷represents a hydrogen atom, then the other of R⁶ and R⁷ does notrepresent an unsubstituted C₁–C₅ alkyl, and (f) when n is 1, X isoxygen, sulphur or NH and A is NHC(O), then R⁶ and R⁷ do not bothsimultaneously represent a hydrogen atom or do not both simultaneouslyrepresent an unsubstituted C₁–C₅ alkyl, or when one of R⁶ and R⁷represents a hydrogen atom, then the other of R⁶ and R⁷ does notrepresent an unsubstituted C₁–C₅ alkyl or —CH₂CH₂OH; or apharmaceutically acceptable salt or solvate thereof.
 3. A compoundaccording to claim 1, wherein m is
 1. 4. A compound according to claim1, wherein A represents NHC(O).
 5. A compound according to claim 1,wherein Ar represents a group of formula (II) or (III).
 6. A compoundaccording to claim 5, wherein Ar represents a group of formula (II). 7.A compound according to claim 1, wherein one of R² and R³ represents ahalogen atom and the other of R² and R³ represents a hydrogen atom.
 8. Acompound according to claim 1, wherein n is
 0. 9. A compound accordingto claim 1, wherein m represents 1; each R¹ represents a hydrogen atom;A represents NHC(O); Ar represents a group

one of R² and R³ represents a halogen atom, and the other of R² and R³represents a hydrogen atom; R⁴ represents a group

X represents an oxygen or sulphur atom or a group >N—R⁸; n is 0 or 1; R⁵represents a C₁–C₃ alkyl group optionally substituted by at least onehydroxyl group; R⁶ and R⁷ each independently represent a hydrogen atom,C₁–C₅ alkyl (optionally substituted by one or two substituentsindependently selected from hydroxyl and (di)-C₁–C₂ alkylamino (itselfoptionally substituted by at least one hydroxyl group)), or C₆cycloalkyl (substituted by at least one hydroxyl group); R⁸ represents ahydrogen atom or a C₂ alkyl group substituted by at least one hydroxylgroup.
 10. A compound according to claim 1, wherein m represents 1; eachR¹ represents a hydrogen atom; A represents NHC(O); Ar represents agroup

one of R² and R³ represents a halogen atom, and the other of R² and R³represents a hydrogen atom; R⁴ represents a group

X represents an oxygen or sulphur atom or a group >N—R⁸; n is 0 or 1; R⁵represents a C₂–C₃ alkyl group optionally substituted by at least onehydroxyl group; R⁶ and R⁷ each independently represent a hydrogen atomor a C₁–C₅ alkyl group optionally substituted by one or two hydroxylgroups; R⁸ represents a hydrogen atom or a C₂ alkyl group substituted byat least one hydroxyl group.
 11. A compound being selected from any oneof:N-(1-Adamantylmethyl)-5-chloro-2-{3-[(3-hydroxypropyl)-amino]propyl}isonicotinamide,N-(1-Adamantylmethyl)-5-chloro-2-{3-[(3-hydroxypropyl)amino]propyl}-isonicotinamidedihydrochloride,N-(1-Adamantylmethyl)-2-chloro-5-{3-[(3-hydroxypropyl)amino]propyl}nicotinamide,N-(1-Adamantylmethyl)-2-chloro-5-(3-{[(1S)-2-hydroxy-1-methylethyl]amino}propyl)nicotinamide,N-(1-Adamantylmethyl)-2-chloro-5-(3-{[(1R)-2-hydroxy-1-methylethyl]amino}propyl)nicotinamide,N-(1-Adamantylmethyl)-2-(3-aminopropyl)-5-chloroisonicotinamidehydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-[3-(ethylamino)propyl]isonicotinamidehydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-({2-[(3-hydroxypropyl)amino]-ethyl}thio)isonicotinamidehydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-(3-{[(1R)-2-hydroxy-1-methylethyl]amino}propyl)isonicotinamide,dihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-(3-{[(1S)-2-hydroxy-1-methylethyl]amino}propyl)isonicotinamide,dihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-{3-[(2-hydroxyethyl)amino]propyl}isonicotinamidehydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-{2-[(3-hydroxypropyl)amino]ethoxy}isonicotinamide,hydrochlorideN-(1-Adamantylmethyl)-5-chloro-2-({2-[(2-hydroxyethyl)amino]ethyl}-amino)isonicotinamidedihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-[3-(isopropylamino)propyl]isonicotinamidedihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-(3-{[(2S)-2-hydroxypropyl]amino}propyl)isonicotinamide,dihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-(3-{[(2R)-2,3-dihydroxypropyl]amino}propyl)isonicotinamide,dihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-(3-{[(2S)-2,3-dihydroxypropyl]amino}propyl)isonicotinamide,dihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-{3-[(4-methylcyclohexyl)amino]propyl}isonicotinamidedihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-{3-[(2-hydroxy-2-methylpropyl)amino]propyl}isonicotinamidedihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-(3-{[(1R)-1-(hydroxymethyl)-2-methylpropyl]amino}propyl)isonicotinamide,dihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-(3-{[2-(methylamino)ethyl]amino}propyl)isonicotinamidedihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-(3-{[3-(methylamino)propyl]amino}propyl)isonicotinamidebis(trifluoroacetate),N-(1-Adamantylmethyl)-5-chloro-2-[3-({2-[(2-hydroxyethyl)amino]ethyl}amino)propyl]isonicotinamidedihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-(3-{[2-(diethylamino)ethyl]amino}propyl)isonicotinamidedihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-(3-{[2-hydroxy-1-(hydroxymethyl)ethyl]amino}propyl)isonicotinamidedihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-{3-[(2-hydroxyethyl)(methyl)amino]propyl}isonicotinamidedihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-{3-[(3-hydroxy-2,2-dimethylpropyl)amino]propyl}isonicotinamidedihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-(3-{[(2R)-2-hydroxypropyl]amino}propyl)isonicotinamide,dihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-({[3-(methylamino)propyl]amino}methyl)isonicotinamidedihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-[({2-[(2-hydroxyethyl)amino]ethyl}amino)methyl]isonicotinamidedihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-({[2-(methylamino)ethyl]amino}methyl)isonicotinamidedihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-{3-[(2-hydroxyethyl)amino]ethyl}isonicotinamidedihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-{3-[(3-hydroxypropyl)amino]ethyl}isonicotinamidedihydrochloride,N-(1-Adamantylmethyl)-5-chloro-2-[3-(methylamino)propyl]isonicotinamidehydrochloride,N-(1-Adamantylmethyl)-5-bromo-2-{[(2S)-2-hydroxy-3-(methylamino)propyl]oxy}isonicotinamide,andN-(1-Adamantylmethyl)-2-({3-[bis(3-hydroxypropyl)amino]propyl}amino)-3-chloroisonicotinamidedihydrochloride, or pharmaceutically acceptable salts and solvatesthereof.
 12. A process for the preparation of a compound according toclaim 1, which comprises: (i) when n is 0 and R⁵ represents CH₂,reacting a compound of formula

wherein R¹⁰ represents —C(O)H or —CH₂L¹, L¹ represents a leaving groupand m, R¹, R² and R³ are as defined in formula (I), or a compound offormula

wherein R¹¹ represents —C(O)H or —CH₂L², L² represents a leaving groupand m, R¹, R² and R³ are as defined in formula (I), or a compound offormula

wherein R¹² represents —C(O)H or —CH₂L³, L³ represents a leaving groupand m, R¹, R² and R³ are as defined in formula (I), with a compound offormula (XIII), HNR⁶R⁷, wherein R⁶ and R⁷ are as defined in formula (I),under reductive amination conditions when R¹⁰, R¹¹ or R¹² represents—C(O)H or in the presence of a suitable base when R¹⁰, R¹¹ or R¹²represents —CH₂L¹, —CH₂L² or —CH₂L³; or (ii) when n is 0, R⁵ is (CH₂)₂and R⁶ and R⁷ are both hydrogen, reacting a compound of formula (X) asdefined in (i) above in which R¹⁰ represents —CH₂L¹, or a compound offormula (XI) as defined in (i) above in which R¹¹ represents —CH₂L², ora compound of formula (XII) as defined in (i) above in which R¹²represents —CH₂L³, with an alkali metal cyanide, followed by ahydrogenation reaction; or (iii) when n is 0, R⁵ is (CH₂)₂ and at leastone of R⁶ and R⁷ is other than hydrogen, reacting a compound as preparedin (ii) above with at least one compound of formula (XIV), R¹³C(O)H,wherein R¹³ represents an optionally substituted C₁–C₆ alkyl or C₃–C₈cycloalkyl group as defined for R⁶ and R⁷ in formula (I), underreductive amination conditions; or (iv) when n is 0 and R⁵ represents aC₃–C₅ alkyl group optionally substituted as defined in formula (I),reacting a compound of formula

wherein R¹⁴ represents a leaving group and m, R¹, R² and R³ are asdefined in formula (I), or a compound of formula

wherein R¹⁵ represents a leaving group and m, A, R¹, R² and R³ are asdefined in formula (I), or a compound of formula

wherein R¹⁶ represents a leaving group and m, R¹, R² and R³ are asdefined in formula (I), with a compound of formula

wherein R^(5′) represents a C₁–C₃ alkyl group optionally substituted asdefined for R⁵ in formula (I) and R⁶ and R⁷ are as defined in formula(I), followed by a hydrogenation reaction; or (v) when n is 0 and R⁵represents a C₃–C₅ alkyl group optionally substituted as defined informula (I), reacting a compound of formula (XV), (XVI) or (XVII) asdefined in (iv) above, with a compound of formula

wherein R^(5′) is as defined in formula (XVIII) in (iv) above, followedby a hydrogenation reaction and then an oxidation reaction and then byreaction with a compound of formula (XIII) as defined in (i) above underreductive amination conditions; or (vi) when n is 1 and X is oxygen or>N—R⁸, reacting a compound of formula

wherein R¹⁷ represents a leaving group and m, A, R¹, R² and R³ are asdefined in formula (I), or a compound of formula

wherein R¹⁸ represents a leaving group and m, A, R¹, R² and R³ are asdefined in formula (I), or a compound of formula

wherein R¹⁹ represents a leaving group and m, A, R¹, R² and R³ are asdefined in formula (I), with a compound of formula

wherein X′ represents oxygen or >N—R⁸ and R⁵, R⁶,R⁷ and R⁸ are asdefined in formula (I); or (vii) when A is NHC(O), n is 1 and X issulphur, reacting a compound of formula

wherein, in each of formulae (XXIV), (XXV) and (XXVI), L⁴ represents aleaving group and R², R³, R⁵, R⁶ and R⁷ are as defined in formula (I),with a compound of formula

wherein m and R¹ are as defined in formula (I); or (viii) when A isC(O)NH, n is 1 and X is sulphur, reacting a compound of formula

wherein, in each of formulae (XXVIII), (XXIX) and (XXX), R², R³, R⁵, R⁶and R⁷ are as defined in formula (I), with a compound of formula

wherein L⁵ represents a leaving group and m and R¹ are as defined informula (I); or (ix) when n is 0 and R⁵ represents a C₂–C₅ alkyl groupsubstituted as defined in formula (I), reacting a compound of formula

or a compound of formula

or a compound of formula

wherein, in each of formulae (XXXII), (XXXIII) and (XXXIV), Y representsa bond or a C₁–C₃ alkyl and m, R¹, R² and R³ are as defined in formula(I), with a compound of formula (XIII) as defined in (i) above, andoptionally thereafter reacting with a C₁–C₆ alkylating agent or with ahalogenating agent; or (x) when n is 0 and R⁵ represents a C₃–C₅ alkylgroup optionally substituted as defined in formula (I), reacting acompound of formula (XV), (XVI) or (XVII) as defined in (iv) above, witha pre-treated compound of formula

in which L⁶ represents a hydrogen atom and R^(5′) represents a C₁–C₃alkyl group optionally substituted as defined for R⁵ in formula (I) andR⁶ and R⁷ are as defined in formula (I), wherein the compound of formula(XXXV) is pre-treated with a hydroborating agent; or (xi) when n is 0and R⁵ represents a C₃–C₅ alkyl group optionally substituted as definedin formula (I), reacting a compound of formula (XV), (XVI) or (XVII) asdefined in (iv) above in the presence of a suitable catalyst, with apre-treated compound of formula

in which L⁷ represents a hydrogen atom and R^(5′) represents a C₁–C₃alkyl group optionally substituted as defined for R⁵ in formula (I) andP is a suitable protecting group, wherein the compound of formula(XXXVIII) is pre-treated with a hydroborating agent, followed by removalof the protecting group, P, in a deprotection reaction, then by anoxidation reaction and then by reaction with a compound of formula(XIII) as defined in (i) above under reductive amination conditions; or(xii) when n is 0 and R⁵is (CH₂)₂, reacting a compound of formula (XV),(XVI) or (XVII) as defined in (iv) above with a compound of formula

wherein R²⁰represents a suitable leaving group, in the presence of asuitable catalyst, followed by reaction with a compound of formula(XIII) as defined in (i) above; or (xiii) when n is 0 and R⁵is CH₂,reacting a compound of formula (XV), (XVI) or (XVII) as defined in (iv)above with a compound of formula (XXXIX) as defined in (xii) above,followed by an oxidation reaction and then by reaction with a compoundof formula (XIII) as defined in (i) above under reductive aminationconditions; and optionally after (i), (ii), (iii), (iv), (v), (vi),(vii), (viii), (ix), (x), (xi), (xii) or (xiii) carrying out one or moreof the following: converting the compound obtained to a further compoundaccording to claim 1 forming a pharmaceutically acceptable salt orsolvate of the compound.
 13. An intermediate compound of formula

wherein T represents —C≡C— or —CH₂CH₂—; R³⁰ represents —CHO, —CH₂OP¹ ora group of formula

P¹ represents a hydrogen atom or a suitable protecting group; P²represents a suitable protecting group; P³ represents a suitableprotecting group; R³¹ represents a C₁–C₅ alkyl group; and m, A, R¹, R²and R³ are as defined in claim
 1. 14. An intermediate compound accordingto claim 13, wherein: m represents 1; A represents NHC(O); eachR¹represents a hydrogen atom; R² represents a halogen atom; and R³represents a hydrogen atom.
 15. A pharmaceutical composition comprisinga compound of formula (I) or a pharmaceutically acceptable salt orsolvate thereof as claimed in claim 1 in association with apharmaceutically acceptable adjuvant, diluent or carrier.
 16. A processfor the preparation of a pharmaceutical composition as claimed in claim15 which comprises mixing a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof as defined in claim1 with a pharmaceutically acceptable adjuvant, diluent or carrier.
 17. Amethod of treating rheumatoid arthritis in a patient, the methodcomprising; administering a compound of formula (I) or apharmaceutically acceptable salt or solvate thereof as claimed in claim1 in the treatment of rheumatoid arthritis.
 18. A method of treating anobstructive airways disease in a patient, the method comprising;administering a compound of formula (I) or a pharmaceutically acceptablesalt or solvate thereof as claimed in claim 1 in the treatment of anobstructive airways disease.
 19. The method according to claim 18,wherein the obstructive airways disease is asthma or chronic obstructivepulmonary disease.